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Xiao B, Chu C, Lin Z, Fang T, Zhou Y, Zhang C, Shan J, Chen S, Li L. Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor- and Cygb-associated signaling pathways. Neural Regen Res 2025; 20:2706-2726. [PMID: 39105365 PMCID: PMC11801291 DOI: 10.4103/nrr.nrr-d-23-01681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 01/30/2024] [Accepted: 03/23/2024] [Indexed: 08/07/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202509000-00031/figure1/v/2024-11-05T132919Z/r/image-tiff A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease. Consequently, enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression. Nonetheless, non-pharmacological interventions aimed at inducing adult neurogenesis are currently limited. Although individual non-pharmacological interventions, such as aerobic exercise, acousto-optic stimulation, and olfactory stimulation, have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease, the therapeutic effect of a strategy that combines these interventions has not been fully explored. In this study, we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months. Amyloid deposition became evident at 4 months, while neurogenesis declined by 6 months, further deteriorating as the disease progressed. However, following a 4-week multifactor stimulation protocol, which encompassed treadmill running (46 min/d, 10 m/min, 6 days per week), 40 Hz acousto-optic stimulation (1 hour/day, 6 days/week), and olfactory stimulation (1 hour/day, 6 days/week), we found a significant increase in the number of newborn cells (5'-bromo-2'-deoxyuridine-positive cells), immature neurons (doublecortin-positive cells), newborn immature neurons (5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells), and newborn astrocytes (5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells). Additionally, the amyloid-beta load in the hippocampus decreased. These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice. Furthermore, cognitive abilities were improved, and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation, as evidenced by Morris water maze, novel object recognition, forced swimming test, and tail suspension test results. Notably, the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2 weeks after treatment cessation. At the molecular level, multifactor stimulation upregulated the expression of neuron-related proteins (NeuN, doublecortin, postsynaptic density protein-95, and synaptophysin), anti-apoptosis-related proteins (Bcl-2 and PARP), and an autophagy-associated protein (LC3B), while decreasing the expression of apoptosis-related proteins (BAX and caspase-9), in the hippocampus of amyloid precursor protein/presenilin 1 mice. These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways. Furthermore, serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis, oxidative damage, and cognition. Collectively, these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.
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Affiliation(s)
- Biao Xiao
- Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
| | - Chaoyang Chu
- Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
| | - Zhicheng Lin
- Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
| | - Tianyuan Fang
- Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
| | - Yuyu Zhou
- Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
| | - Chuxia Zhang
- Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
| | - Jianghui Shan
- Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
| | - Shiyu Chen
- Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
| | - Liping Li
- Department of Physiology and Pharmacology, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
- Ningbo Key Laboratory of Behavioral Neuroscience, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China
- Key Laboratory of Addiction Research of Zhejiang Province, Ningbo, Zhejiang Province, China
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Quansah E, Vatsa N, Ensink E, Brown J, Cave T, Aguileta M, Schulz E, Lindquist A, Gilliland C, Steiner JA, Escobar Galvis ML, Milčiūtė M, Henderson MX, Brundin P, Brundin L, Marshall LL, Gordevicius J. Tet2 loss and enhanced ciliogenesis suppress α-synuclein pathology. Acta Neuropathol Commun 2025; 13:71. [PMID: 40189544 PMCID: PMC11974201 DOI: 10.1186/s40478-025-01988-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 03/24/2025] [Indexed: 04/09/2025] Open
Abstract
There are no approved treatments that slow Parkinson's disease (PD) progression and therefore it is important to identify novel pathogenic mechanisms that can be targeted. Loss of the epigenetic marker, Tet2 appears to have some beneficial effects in PD models, but the underlying mechanism of action is not well understood. We performed an unbiased transcriptomic analysis of cortical neurons isolated from patients with PD to identify dysregulated pathways and determine their potential contributions to the disease process. We discovered that genes associated with primary cilia, non-synaptic sensory and signaling organelles, are upregulated in both early and late stage PD patients. Enhancing ciliogenesis in primary cortical neurons via sonic hedgehog signaling suppressed the accumulation of α-synuclein pathology in vitro. Interestingly, deletion of Tet2 in mice also enhanced the expression of primary cilia and sonic hedgehog signaling genes and reduced the accumulation of α-synuclein pathology and dopamine neuron degeneration in vivo. Our findings demonstrate the crucial role of TET2 loss in regulating ciliogenesis and potentially affecting the progression of PD pathology.
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Affiliation(s)
- Emmanuel Quansah
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.
- Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA.
| | - Naman Vatsa
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Elizabeth Ensink
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Jaycie Brown
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Tyce Cave
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Miguel Aguileta
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Emily Schulz
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Allison Lindquist
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Carla Gilliland
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Jennifer A Steiner
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | | | | | - Michael X Henderson
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
| | - Patrik Brundin
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
- Roche Pharma Research and Early Development (pRED), Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland
| | - Lena Brundin
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA
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Dvoriantchikova G, Moulin C, Fleishaker M, Almeida V, Pelaez D, Lam BL, Ivanov D. Genetic ablation of the TET family in retinal progenitor cells impairs photoreceptor development and leads to blindness. Proc Natl Acad Sci U S A 2025; 122:e2420091122. [PMID: 40053367 PMCID: PMC11912455 DOI: 10.1073/pnas.2420091122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 01/31/2025] [Indexed: 03/19/2025] Open
Abstract
The retina is responsible for converting light into electrical signals that, when transmitted to the brain, create the sensation of vision. The mammalian retina is epigenetically unique since the differentiation of retinal progenitor cells (RPCs) into retinal cells is accompanied by a decrease in DNA methylation in the promoters of many genes important for retinal development and function. However, the pathway responsible for DNA demethylation and its role in retinal development and function were unknown. We hypothesized that the Ten-Eleven Translocation (TET) family of dioxygenases plays a key role in this pathway. To this end, we knocked out the TET family in RPCs and characterized the TET-deficient and control retinas using various approaches including electron microscopy, electroretinogram tests, TUNEL, RNA-seq, WGBS, and 5hmC-Seal. We found that while the TET-dependent DNA demethylation pathway contributes to the development of many retinal cell types, it is the most significant contributor to rod and cone photoreceptor development and function. We found that genetic ablation of TET enzymes in RPCs prevents demethylation and the activity of genes essential for rod specification and for rod and cone maturation. Reduced activity of genes responsible for rod specification results in the TET-deficient retina being depleted of these neurons. Meanwhile, reduced activity of genes responsible for rod and cone maturation leads to the underdevelopment or complete absence of outer segments and synaptic termini in the TET-deficient photoreceptors, which results in loss of their function and leads to blindness. These function-deprived, underdeveloped photoreceptors die over time, leading to retinal dystrophy.
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Affiliation(s)
- Galina Dvoriantchikova
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Chloe Moulin
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Michelle Fleishaker
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Vania Almeida
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL33136
| | - Daniel Pelaez
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Byron L. Lam
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL33136
| | - Dmitry Ivanov
- Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL33136
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL33136
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Zhao X, Sun Q, Shou Y, Chen W, Wang M, Qu W, Huang X, Li Y, Wang C, Gu Y, Ji C, Shu Q, Li X. A human forebrain organoid model reveals the essential function of GTF2IRD1-TTR-ERK axis for the neurodevelopmental deficits of Williams syndrome. eLife 2024; 13:RP98081. [PMID: 39671308 PMCID: PMC11643624 DOI: 10.7554/elife.98081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2024] Open
Abstract
Williams syndrome (WS; OMIM#194050) is a rare disorder, which is caused by the microdeletion of one copy of 25-27 genes, and WS patients display diverse neuronal deficits. Although remarkable progresses have been achieved, the mechanisms for these distinct deficits are still largely unknown. Here, we have shown that neural progenitor cells (NPCs) in WS forebrain organoids display abnormal proliferation and differentiation capabilities, and synapse formation. Genes with altered expression are related to neuronal development and neurogenesis. Single cell RNA-seq (scRNA-seq) data analysis revealed 13 clusters in healthy control and WS organoids. WS organoids show an aberrant generation of excitatory neurons. Mechanistically, the expression of transthyretin (TTR) are remarkably decreased in WS forebrain organoids. We have found that GTF2IRD1 encoded by one WS associated gene GTF2IRD1 binds to TTR promoter regions and regulates the expression of TTR. In addition, exogenous TTR can activate ERK signaling and rescue neurogenic deficits of WS forebrain organoids. Gtf2ird1-deficient mice display similar neurodevelopmental deficits as observed in WS organoids. Collectively, our study reveals critical function of GTF2IRD1 in regulating neurodevelopment of WS forebrain organoids and mice through regulating TTR-ERK pathway.
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Affiliation(s)
- Xingsen Zhao
- The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang UniversityHangzhouChina
- The Institute of Translational Medicine, School of Medicine, Zhejiang UniversityHangzhouChina
- Binjiang Institute of Zhejiang UniversityHangzhouChina
| | - Qihang Sun
- The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang UniversityHangzhouChina
- The Institute of Translational Medicine, School of Medicine, Zhejiang UniversityHangzhouChina
| | - Yikai Shou
- The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang UniversityHangzhouChina
| | - Weijun Chen
- The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang UniversityHangzhouChina
| | - Mengxuan Wang
- The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang UniversityHangzhouChina
- The Institute of Translational Medicine, School of Medicine, Zhejiang UniversityHangzhouChina
| | - Wenzheng Qu
- The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang UniversityHangzhouChina
| | - Xiaoli Huang
- The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang UniversityHangzhouChina
| | - Ying Li
- The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang UniversityHangzhouChina
| | - Chao Wang
- Center of Stem Cell and Regenerative Medicine, and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
| | - Yan Gu
- Center of Stem Cell and Regenerative Medicine, and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
| | - Chai Ji
- The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang UniversityHangzhouChina
| | - Qiang Shu
- The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang UniversityHangzhouChina
| | - Xuekun Li
- The Children's Hospital, National Clinical Research Center for Child Health, School of Medicine, Zhejiang UniversityHangzhouChina
- The Institute of Translational Medicine, School of Medicine, Zhejiang UniversityHangzhouChina
- Binjiang Institute of Zhejiang UniversityHangzhouChina
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5
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Wang R, Ji L, Yuan S, Liu X, Liang Z, Chen W, Wang B, Hu S, Liu Z, Zeng Z, Song Y, Wu T, Chen B. Microglial forkhead box O3a deficiency attenuates LPS-induced neuro-inflammation and depressive-like behaviour through regulating the expression of peroxisome proliferator-activated receptor-γ. Br J Pharmacol 2024; 181:3908-3925. [PMID: 38881194 DOI: 10.1111/bph.16474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 03/15/2024] [Accepted: 03/17/2024] [Indexed: 06/18/2024] Open
Abstract
BACKGROUND AND PURPOSE Depression is closely linked with microglial activation and neuro-inflammation. Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays an important role in M2 activation of microglia. Forkhead box (FOX) O3a has been implicated in the regulation of mood-relevant behaviour. However, little is known about the inflammatory mechanisms of in the microglia of the brain. Here, we have investigated the role of microglial FOXO3a/PPAR-γ in the development of depression. EXPERIMENTAL APPROACH The effect of FOXO3a on microglia inflammation was analysed in vitro and in lipopolysaccharide (LPS)-induced depression-like behaviours in vivo. ChIP-seq and Dual-luciferase reporter assays were used to confirm the interaction between FOXO3a and PPAR-γ. Behavioural changes were measured, while inflammatory cytokines, microglial phenotype and morphological properties were determined by ELISA, qRT-PCR, western blotting and immunostaining. KEY RESULTS Overexpression of FOXO3a significantly attenuated expression of PPAR-γ and enhanced the microglial polarization towards the M1 phenotype, while knockdown of FOXO3a had the opposite effect. FOXO3a binds to the promoters of PPAR-γ and decreases its transcription activity. Importantly, deacetylation and activation of FOXO3a regulate LPS-induced neuro-inflammation by inhibiting the expression of PPAR-γ in microglia cells, supporting the antidepressant potential of histone deacetylase inhibitors. Microglial FOXO3a deficiency in mice alleviated LPS-induced neuro-inflammation and depression-like behaviours but failed to reduce anxiety behaviour, whereas pharmacological inhibition of PPAR-γ by GW9662 restored LPS-induced microglial activation and depressive-like behaviours in microglial FOXO3a-deficient mice. CONCLUSION AND IMPLICATIONS FOXO3a/PPAR-γ axis plays an important role in microglial activation and depression, identifying a new therapeutic avenue for the treatment of major depression.
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Affiliation(s)
- Rikang Wang
- Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Lianru Ji
- Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Disease with Mental Disorders); Key Laboratory of Depression Animal Model Based on TCM syndrome, Jiangxi Administration of Traditional Chinese Medicine; Key Laboratory of TCM for Prevention and Treatment of Brain Diseases with Cognitive Dysfunction, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Shun Yuan
- Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Disease with Mental Disorders); Key Laboratory of Depression Animal Model Based on TCM syndrome, Jiangxi Administration of Traditional Chinese Medicine; Key Laboratory of TCM for Prevention and Treatment of Brain Diseases with Cognitive Dysfunction, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Xiamin Liu
- Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Disease with Mental Disorders); Key Laboratory of Depression Animal Model Based on TCM syndrome, Jiangxi Administration of Traditional Chinese Medicine; Key Laboratory of TCM for Prevention and Treatment of Brain Diseases with Cognitive Dysfunction, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Zhi Liang
- Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Wenjing Chen
- Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Bocheng Wang
- Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Suifa Hu
- Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Disease with Mental Disorders); Key Laboratory of Depression Animal Model Based on TCM syndrome, Jiangxi Administration of Traditional Chinese Medicine; Key Laboratory of TCM for Prevention and Treatment of Brain Diseases with Cognitive Dysfunction, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Zhiping Liu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China
| | - Zhiwen Zeng
- Department for Bipolar Disorders, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, China
| | - Yonggui Song
- Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Disease with Mental Disorders); Key Laboratory of Depression Animal Model Based on TCM syndrome, Jiangxi Administration of Traditional Chinese Medicine; Key Laboratory of TCM for Prevention and Treatment of Brain Diseases with Cognitive Dysfunction, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Tao Wu
- Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Baodong Chen
- Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China
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6
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Ma X, Thela SR, Zhao F, Yao B, Wen Z, Jin P, Zhao J, Chen L. Deep5hmC: predicting genome-wide 5-hydroxymethylcytosine landscape via a multimodal deep learning model. Bioinformatics 2024; 40:btae528. [PMID: 39196755 PMCID: PMC11379467 DOI: 10.1093/bioinformatics/btae528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 08/09/2024] [Accepted: 08/27/2024] [Indexed: 08/30/2024] Open
Abstract
MOTIVATION 5-Hydroxymethylcytosine (5hmC), a crucial epigenetic mark with a significant role in regulating tissue-specific gene expression, is essential for understanding the dynamic functions of the human genome. Despite its importance, predicting 5hmC modification across the genome remains a challenging task, especially when considering the complex interplay between DNA sequences and various epigenetic factors such as histone modifications and chromatin accessibility. RESULTS Using tissue-specific 5hmC sequencing data, we introduce Deep5hmC, a multimodal deep learning framework that integrates both the DNA sequence and epigenetic features such as histone modification and chromatin accessibility to predict genome-wide 5hmC modification. The multimodal design of Deep5hmC demonstrates remarkable improvement in predicting both qualitative and quantitative 5hmC modification compared to unimodal versions of Deep5hmC and state-of-the-art machine learning methods. This improvement is demonstrated through benchmarking on a comprehensive set of 5hmC sequencing data collected at four developmental stages during forebrain organoid development and across 17 human tissues. Compared to DeepSEA and random forest, Deep5hmC achieves close to 4% and 17% improvement of Area Under the Receiver Operating Characteristic (AUROC) across four forebrain developmental stages, and 6% and 27% across 17 human tissues for predicting binary 5hmC modification sites; and 8% and 22% improvement of Spearman correlation coefficient across four forebrain developmental stages, and 17% and 30% across 17 human tissues for predicting continuous 5hmC modification. Notably, Deep5hmC showcases its practical utility by accurately predicting gene expression and identifying differentially hydroxymethylated regions (DhMRs) in a case-control study of Alzheimer's disease (AD). Deep5hmC significantly improves our understanding of tissue-specific gene regulation and facilitates the development of new biomarkers for complex diseases. AVAILABILITY AND IMPLEMENTATION Deep5hmC is available via https://github.com/lichen-lab/Deep5hmC.
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Affiliation(s)
- Xin Ma
- Department of Biostatistics, University of Florida, Gainesville, FL 32603, United States
| | - Sai Ritesh Thela
- Department of Biostatistics, University of Florida, Gainesville, FL 32603, United States
| | - Fengdi Zhao
- Department of Biostatistics, University of Florida, Gainesville, FL 32603, United States
| | - Bing Yao
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Zhexing Wen
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Peng Jin
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Jinying Zhao
- Department of Epidemiology, University of Florida, Gainesville, FL 32603, United States
| | - Li Chen
- Department of Biostatistics, University of Florida, Gainesville, FL 32603, United States
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Zhao T, Hong Y, Yan B, Huang S, Ming GL, Song H. Epigenetic maintenance of adult neural stem cell quiescence in the mouse hippocampus via Setd1a. Nat Commun 2024; 15:5674. [PMID: 38971831 PMCID: PMC11227589 DOI: 10.1038/s41467-024-50010-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 06/25/2024] [Indexed: 07/08/2024] Open
Abstract
Quiescence, a hallmark of adult neural stem cells (NSCs), is required for maintaining the NSC pool to support life-long continuous neurogenesis in the adult dentate gyrus (DG). Whether long-lasting epigenetic modifications maintain NSC quiescence over the long term in the adult DG is not well-understood. Here we show that mice with haploinsufficiency of Setd1a, a schizophrenia risk gene encoding a histone H3K4 methyltransferase, develop an enlarged DG with more dentate granule cells after young adulthood. Deletion of Setd1a specifically in quiescent NSCs in the adult DG promotes their activation and neurogenesis, which is countered by inhibition of the histone demethylase LSD1. Mechanistically, RNA-sequencing and CUT & RUN analyses of cultured quiescent adult NSCs reveal Setd1a deletion-induced transcriptional changes and many Setd1a targets, among which down-regulation of Bhlhe40 promotes quiescent NSC activation in the adult DG in vivo. Together, our study reveals a Setd1a-dependent epigenetic mechanism that sustains NSC quiescence in the adult DG.
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Affiliation(s)
- Ting Zhao
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philedaphia, PA, 19104, USA
| | - Yan Hong
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philedaphia, PA, 19104, USA
| | - Bowen Yan
- Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Suming Huang
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA
| | - Guo-Li Ming
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philedaphia, PA, 19104, USA.
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philedaphia, PA, 19104, USA.
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philedaphia, PA, 19104, USA.
- Institute for Regenerative Medicine, University of Pennsylvania, Philedaphia, PA, 19104, USA.
| | - Hongjun Song
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philedaphia, PA, 19104, USA.
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philedaphia, PA, 19104, USA.
- Institute for Regenerative Medicine, University of Pennsylvania, Philedaphia, PA, 19104, USA.
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philedaphia, PA, 19104, USA.
- The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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8
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Ma X, Thela SR, Zhao F, Yao B, Wen Z, Jin P, Zhao J, Chen L. Deep5hmC: Predicting genome-wide 5-Hydroxymethylcytosine landscape via a multimodal deep learning model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.04.583444. [PMID: 38496575 PMCID: PMC10942288 DOI: 10.1101/2024.03.04.583444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
5-hydroxymethylcytosine (5hmC), a critical epigenetic mark with a significant role in regulating tissue-specific gene expression, is essential for understanding the dynamic functions of the human genome. Using tissue-specific 5hmC sequencing data, we introduce Deep5hmC, a multimodal deep learning framework that integrates both the DNA sequence and the histone modification information to predict genome-wide 5hmC modification. The multimodal design of Deep5hmC demonstrates remarkable improvement in predicting both qualitative and quantitative 5hmC modification compared to unimodal versions of Deep5hmC and state-of-the-art machine learning methods. This improvement is demonstrated through benchmarking on a comprehensive set of 5hmC sequencing data collected at four time points during forebrain organoid development and across 17 human tissues. Notably, Deep5hmC showcases its practical utility by accurately predicting gene expression and identifying differentially hydroxymethylated regions in a case-control study of Alzheimer's disease.
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Affiliation(s)
- Xin Ma
- Department of Biostatistics, University of Florida, Gainesville, FL, 32603, USA
| | - Sai Ritesh Thela
- Department of Biostatistics, University of Florida, Gainesville, FL, 32603, USA
| | - Fengdi Zhao
- Department of Biostatistics, University of Florida, Gainesville, FL, 32603, USA
| | - Bing Yao
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Zhexing Wen
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Peng Jin
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Jinying Zhao
- Department of Epidemiology, University of Florida, Gainesville, FL, 32603, USA
| | - Li Chen
- Department of Biostatistics, University of Florida, Gainesville, FL, 32603, USA
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9
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Xia M, Yan R, Wang W, Zhang M, Miao Z, Wan B, Xu X. GID complex regulates the differentiation of neural stem cells by destabilizing TET2. Front Med 2023; 17:1204-1218. [PMID: 37707676 DOI: 10.1007/s11684-023-1007-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 04/27/2023] [Indexed: 09/15/2023]
Abstract
Brain development requires a delicate balance between self-renewal and differentiation in neural stem cells (NSC), which rely on the precise regulation of gene expression. Ten-eleven translocation 2 (TET2) modulates gene expression by the hydroxymethylation of 5-methylcytosine in DNA as an important epigenetic factor and participates in the neuronal differentiation. Yet, the regulation of TET2 in the process of neuronal differentiation remains unknown. Here, the protein level of TET2 was reduced by the ubiquitin-proteasome pathway during NSC differentiation, in contrast to mRNA level. We identified that TET2 physically interacts with the core subunits of the glucose-induced degradation-deficient (GID) ubiquitin ligase complex, an evolutionarily conserved ubiquitin ligase complex and is ubiquitinated by itself. The protein levels of GID complex subunits increased reciprocally with TET2 level upon NSC differentiation. The silencing of the core subunits of the GID complex, including WDR26 and ARMC8, attenuated the ubiquitination and degradation of TET2, increased the global 5-hydroxymethylcytosine levels, and promoted the differentiation of the NSC. TET2 level increased in the brain of the Wdr26+/- mice. Our results illustrated that the GID complex negatively regulates TET2 protein stability, further modulates NSC differentiation, and represents a novel regulatory mechanism involved in brain development.
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Affiliation(s)
- Meiling Xia
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- Institute of Neuroscience, Soochow University, Suzhou, 215006, China
| | - Rui Yan
- Institute of Neuroscience, Soochow University, Suzhou, 215006, China
| | - Wenjuan Wang
- Institute of Neuroscience, Soochow University, Suzhou, 215006, China
| | - Meng Zhang
- Institute of Neuroscience, Soochow University, Suzhou, 215006, China
| | - Zhigang Miao
- Institute of Neuroscience, Soochow University, Suzhou, 215006, China
| | - Bo Wan
- Institute of Neuroscience, Soochow University, Suzhou, 215006, China.
| | - Xingshun Xu
- Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
- Institute of Neuroscience, Soochow University, Suzhou, 215006, China.
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215123, China.
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10
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Gao J, Wang H, Shen J, Liu X, Zhu X, Huang C, Li G, Sun Y, Liu Z, Sun YE, Liu H. Mutual regulation between GDF11 and TET2 prevents senescence of mesenchymal stem cells. J Cell Physiol 2023; 238:2827-2840. [PMID: 37801347 DOI: 10.1002/jcp.31132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 09/15/2023] [Accepted: 09/20/2023] [Indexed: 10/07/2023]
Abstract
Growth differentiation factor 11 (GDF11) is a putative systemic rejuvenation factor. In this study, we characterized the mechanism by which GDF11 reversed aging of mesenchymal stem cells (MSCs). In culture, aged MSCs proliferate slower and are positive for senescence markers senescence-associated β-galactosidase and P16ink4a . They have shortened telomeres, decreased GDF11 expression, and reduced osteogenic potential. GDF11 can block MSC aging in vitro and reverse age-dependent bone loss in vivo. The antiaging effect of GDF11 is via activation of the Smad2/3-PI3K-AKT-mTOR pathway. Unexpectedly, GDF11 also upregulated a DNA demethylase Tet2, which served as a key mediator for GDF11 to autoregulate itself via demethylation of the GDF11 promoter. Mutation of Tet2 facilitates MSC aging by blocking GDF11 expression. Mutagenesis of Tet2-regulated CpG sites also blocks GDF11 expression, leading to MSC aging. Together, a novel mutual regulatory relationship between GDF11 and an epigenetic factor Tet2 unveiled their antiaging roles.
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Affiliation(s)
- Jiaming Gao
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hao Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Junyan Shen
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaojing Liu
- Translational Center for Stem Cell Research, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoqi Zhu
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ce Huang
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Gongchen Li
- Department of Implantology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School of Stomatology, Tongji University, Shanghai, China
| | - Yao Sun
- Department of Implantology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School of Stomatology, Tongji University, Shanghai, China
| | - Zhongmin Liu
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yi Eve Sun
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Translational Center for Stem Cell Research, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Implantology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, School of Stomatology, Tongji University, Shanghai, China
- Department of Psychiatry and Biobehavioral Sciences, UCLA Medical School, Los Angeles, California, USA
| | - Hailiang Liu
- Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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11
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Lv H, Gao Z, Wang Y, Chen S, Liu P, Xie Y, Guan M, Cong J, Xu Y. Metformin Improves Comorbid Depressive Symptoms in Mice with Allergic Rhinitis by Reducing Olfactory Bulb Damage. Neurochem Res 2023; 48:3639-3651. [PMID: 37574530 DOI: 10.1007/s11064-023-04012-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/06/2023] [Accepted: 08/08/2023] [Indexed: 08/15/2023]
Abstract
Allergic rhinitis (AR) is a widespread disease that is frequently comorbid with depression. However, the mechanisms and treatments for depression in AR remain underexplored. Metformin, a widely used antidiabetic drug, has shown antidepressant effects. The aim of this study was to explore the effects and potential mechanisms of metformin on depression-like behaviors in an AR mouse model. In the present study, mice were sensitized and challenged with ovalbumin (OVA) to induce AR. Results showed that mice with AR exhibited significant depression-like behavior which was attenuated by metformin. In addition, the levels of expression of synaptic plasticity markers (anti-microtubule-associated protein 2, synaptophysin, postsynaptic density protein 95), neurogenesis markers (doublecortin and Ki-67), and brain-derived neurotrophic factor were decreased in the olfactory bulb (OB) of mice with AR, while metformin ameliorated all these alterations and reduced apoptosis in the OB of these mice. Furthermore, it enhanced the phosphorylation of AMP-activated kinase (AMPK) and the levels of ten-eleven translocation 2 (TET2) and 5-hydroxymethylcytosine in the OB. In conclusion, our findings suggest that metformin might be a viable strategy for treating AR-related depression, possibly by modulating neuroplasticity, neurogenesis, apoptosis, and BDNF signaling in the OB via the AMPK/TET2 pathway.
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Affiliation(s)
- Hao Lv
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Ziang Gao
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Research Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Yunfei Wang
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Siyuan Chen
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Peiqiang Liu
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Research Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Yulie Xie
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Mengting Guan
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Jianchao Cong
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China
| | - Yu Xu
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China.
- Department of Rhinology and Allergy, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China.
- Research Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan, Hubei, 430060, China.
- Hubei Province Key Laboratory of Allergy and Immunology, Wuhan, Hubei, 430060, China.
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12
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Singh N, Siebzehnrubl FA, Martinez-Garay I. Transcriptional control of embryonic and adult neural progenitor activity. Front Neurosci 2023; 17:1217596. [PMID: 37588515 PMCID: PMC10426504 DOI: 10.3389/fnins.2023.1217596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 07/10/2023] [Indexed: 08/18/2023] Open
Abstract
Neural precursors generate neurons in the embryonic brain and in restricted niches of the adult brain in a process called neurogenesis. The precise control of cell proliferation and differentiation in time and space required for neurogenesis depends on sophisticated orchestration of gene transcription in neural precursor cells. Much progress has been made in understanding the transcriptional regulation of neurogenesis, which relies on dose- and context-dependent expression of specific transcription factors that regulate the maintenance and proliferation of neural progenitors, followed by their differentiation into lineage-specified cells. Here, we review some of the most widely studied neurogenic transcription factors in the embryonic cortex and neurogenic niches in the adult brain. We compare functions of these transcription factors in embryonic and adult neurogenesis, highlighting biochemical, developmental, and cell biological properties. Our goal is to present an overview of transcriptional regulation underlying neurogenesis in the developing cerebral cortex and in the adult brain.
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Affiliation(s)
- Niharika Singh
- Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom
- European Cancer Stem Cell Research Institute, Cardiff University School of Biosciences, Cardiff, United Kingdom
| | - Florian A. Siebzehnrubl
- European Cancer Stem Cell Research Institute, Cardiff University School of Biosciences, Cardiff, United Kingdom
| | - Isabel Martinez-Garay
- Division of Neuroscience, School of Biosciences, Cardiff University, Cardiff, United Kingdom
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13
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Zocher S, Toda T. Epigenetic aging in adult neurogenesis. Hippocampus 2023; 33:347-359. [PMID: 36624660 DOI: 10.1002/hipo.23494] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/11/2022] [Accepted: 12/06/2022] [Indexed: 01/11/2023]
Abstract
Neural stem cells (NSCs) in the hippocampus generate new neurons throughout life, which functionally contribute to cognitive flexibility and mood regulation. Yet adult hippocampal neurogenesis substantially declines with age and age-related impairments in NSC activity underlie this reduction. Particularly, increased NSC quiescence and consequently reduced NSC proliferation are considered to be major drivers of the low neurogenesis levels in the aged brain. Epigenetic regulators control the gene expression programs underlying NSC quiescence, proliferation and differentiation and are hence critical to the regulation of adult neurogenesis. Epigenetic alterations have also emerged as central hallmarks of aging, and recent studies suggest the deterioration of the NSC-specific epigenetic landscape as a driver of the age-dependent decline in adult neurogenesis. In this review, we summarize the recently accumulating evidence for a role of epigenetic dysregulation in NSC aging and propose perspectives for future research directions.
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Affiliation(s)
- Sara Zocher
- Nuclear Architecture in Neural Plasticity and Aging Laboratory, German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany
| | - Tomohisa Toda
- Nuclear Architecture in Neural Plasticity and Aging Laboratory, German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany
- Institute of Medical Physics and Microtissue Engineering, Faculty of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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14
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Zima L, West R, Smolen P, Kobori N, Hergenroeder G, Choi HA, Moore AN, Redell JB, Dash PK. Epigenetic Modifications and Their Potential Contribution to Traumatic Brain Injury Pathobiology and Outcome. J Neurotrauma 2022; 39:1279-1288. [PMID: 35481812 PMCID: PMC9529317 DOI: 10.1089/neu.2022.0128] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Epigenetic information is not permanently encoded in the DNA sequence, but rather consists of reversible, heritable modifications that regulate the gene expression profile of a cell. Epigenetic modifications can result in cellular changes that can be long lasting and include DNA methylation, histone methylation, histone acetylation, and RNA methylation. As epigenetic modifications are reversible, the enzymes that add (epigenetic writers), the proteins that decode (epigenetic readers), and the enzymes that remove (epigenetic erasers) these modifications can be targeted to alter cellular function and disease biology. While epigenetic modifications and their contributions are intense topics of current research in the context of a number of diseases, including cancer, inflammatory diseases, and Alzheimer disease, the study of epigenetics in the context of traumatic brain injury (TBI) is in its infancy. In this review, we will summarize the experimental and clinical findings demonstrating that TBI triggers epigenetic modifications, with a focus on changes in DNA methylation, histone methylation, and the translational utility of the universal methyl donor S-adenosylmethionine (SAM). Finally, we will review the evidence for using methyl donors as possible treatments for TBI-associated pathology and outcome.
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Affiliation(s)
- Laura Zima
- Department of Neurological Surgery, University of Texas Health Science Center McGovern Medical School, Houston, Texas, USA
| | - Rebecca West
- Department of Neurobiology and Anatomy, University of Texas Health Science Center McGovern Medical School, Houston, Texas, USA
| | - Paul Smolen
- Department of Neurobiology and Anatomy, University of Texas Health Science Center McGovern Medical School, Houston, Texas, USA
| | - Nobuhide Kobori
- Department of Neurobiology and Anatomy, University of Texas Health Science Center McGovern Medical School, Houston, Texas, USA
| | - Georgene Hergenroeder
- Department of Neurological Surgery, University of Texas Health Science Center McGovern Medical School, Houston, Texas, USA
| | - HuiMahn A. Choi
- Department of Neurological Surgery, University of Texas Health Science Center McGovern Medical School, Houston, Texas, USA
| | - Anthony N. Moore
- Department of Neurobiology and Anatomy, University of Texas Health Science Center McGovern Medical School, Houston, Texas, USA
| | - John B. Redell
- Department of Neurobiology and Anatomy, University of Texas Health Science Center McGovern Medical School, Houston, Texas, USA
| | - Pramod K. Dash
- Department of Neurobiology and Anatomy, University of Texas Health Science Center McGovern Medical School, Houston, Texas, USA
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15
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Huang X, Guo H, Cheng X, Zhang J, Qu W, Ding Q, Sun Q, Shu Q, Li X. NAD+ Modulates the Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells via Akt Signaling Pathway. Cells 2022; 11:cells11081283. [PMID: 35455963 PMCID: PMC9029130 DOI: 10.3390/cells11081283] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 04/01/2022] [Accepted: 04/02/2022] [Indexed: 11/16/2022] Open
Abstract
Nicotinamide adenine dinucleotide hydrate (NAD+) acts as the essential component of the tricarboxylic citric acid (TCA) cycle and has important functions in diverse biological processes. However, the roles of NAD+ in regulating adult neural stem/progenitor cells (aNSPCs) remain largely unknown. Here, we show that NAD+ exposure leads to the reduced proliferation and neuronal differentiation of aNSPCs and induces the apoptosis of aNSPCs. In addition, NAD+ exposure inhibits the morphological development of neurons. Mechanistically, RNA sequencing revealed that the transcriptome of aNSPCs is altered by NAD+ exposure. NAD+ exposure significantly decreases the expression of multiple genes related to ATP metabolism and the PI3k-Akt signaling pathway. Collectively, our findings provide some insights into the roles and mechanisms in which NAD+ regulates aNSPCs and neuronal development.
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Affiliation(s)
- Xiaoli Huang
- The Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China; (X.H.); (H.G.); (X.C.); (J.Z.); (W.Q.); (Q.D.); (Q.S.)
- The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Hongfeng Guo
- The Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China; (X.H.); (H.G.); (X.C.); (J.Z.); (W.Q.); (Q.D.); (Q.S.)
- The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Xuejun Cheng
- The Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China; (X.H.); (H.G.); (X.C.); (J.Z.); (W.Q.); (Q.D.); (Q.S.)
- The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Jinyu Zhang
- The Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China; (X.H.); (H.G.); (X.C.); (J.Z.); (W.Q.); (Q.D.); (Q.S.)
- The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Wenzheng Qu
- The Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China; (X.H.); (H.G.); (X.C.); (J.Z.); (W.Q.); (Q.D.); (Q.S.)
| | - Qianyun Ding
- The Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China; (X.H.); (H.G.); (X.C.); (J.Z.); (W.Q.); (Q.D.); (Q.S.)
| | - Qihang Sun
- The Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China; (X.H.); (H.G.); (X.C.); (J.Z.); (W.Q.); (Q.D.); (Q.S.)
- The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Qiang Shu
- The Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China; (X.H.); (H.G.); (X.C.); (J.Z.); (W.Q.); (Q.D.); (Q.S.)
- Correspondence: (Q.S.); (X.L.)
| | - Xuekun Li
- The Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China; (X.H.); (H.G.); (X.C.); (J.Z.); (W.Q.); (Q.D.); (Q.S.)
- The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
- Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310029, China
- Correspondence: (Q.S.); (X.L.)
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16
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Dvoriantchikova G, Lypka KR, Ivanov D. The Potential Role of Epigenetic Mechanisms in the Development of Retinitis Pigmentosa and Related Photoreceptor Dystrophies. Front Genet 2022; 13:827274. [PMID: 35360866 PMCID: PMC8961674 DOI: 10.3389/fgene.2022.827274] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/25/2022] [Indexed: 12/13/2022] Open
Abstract
Retinitis pigmentosa and related photoreceptor dystrophies (RPRPD) are rare retinal diseases caused by hereditary gene mutations resulting in photoreceptor death, followed by vision loss. While numerous genes involved in these diseases have been identified, many cases have still not been associated with any gene, indicating that new mechanisms may be involved in the pathogenesis of these photoreceptor dystrophies. Many genes associated with RPRPD regulate photoreceptor specification and maturation in the developing retina. Since retinal development begins with a population of equivalent, proliferating retinal progenitor cells (RPCs) having a specific “competence” in generating all types of retinal neurons, including cone and rod photoreceptors, we tested the epigenetic changes in promoters of genes required for photoreceptor development and genes associated with RPRPD during RPC differentiation into cone and rod photoreceptors. We found that promoters of many of these genes are epigenetically repressed in RPCs but have no epigenetic restrictions in photoreceptors. Our findings also suggest that DNA methylation as an epigenetic mark, and DNA demethylation as a process, are more important than other epigenetic marks or mechanisms in the pathogenesis of these diseases. Most notably, irregularities in the DNA demethylation process during the RPC-to-photoreceptor transition may significantly contribute to retinitis pigmentosa (RP) pathogenesis since genes with hypermethylated promoters in RPCs account for at least 40% of autosomal recessive RP cases and at least 30% of autosomal dominant RP cases. Thus, we proposed an epigenetic model according to which unsuccessful demethylation of regulatory sequences (e.g., promoters, enhancers) of genes required for photoreceptor development, maturation, and function during the RPC-to-photoreceptor transition may reduce or even eliminate their activity, leading to RPRPD without any inheritable mutations in these genes.
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Affiliation(s)
- Galina Dvoriantchikova
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Karin Rose Lypka
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Dmitry Ivanov
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States
- *Correspondence: Dmitry Ivanov,
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17
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Pronier E, Imanci A, Selimoglu-Buet D, Badaoui B, Itzykson R, Roger T, Jego C, Naimo A, Francillette M, Breckler M, Wagner-Ballon O, Figueroa ME, Aglave M, Gautheret D, Porteu F, Bernard OA, Vainchenker W, Delhommeau F, Solary E, Droin NM. Macrophage migration inhibitory factor is overproduced through EGR1 in TET2 low resting monocytes. Commun Biol 2022; 5:110. [PMID: 35115654 PMCID: PMC8814058 DOI: 10.1038/s42003-022-03057-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 01/06/2022] [Indexed: 12/14/2022] Open
Abstract
Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in age-related clonal hematopoiesis as well as in chronic myelomonocytic leukemia (CMML). In addition to being a pre-malignant state, TET2 mutated clones are associated with an increased risk of death from cardiovascular disease, which could involve cytokine/chemokine overproduction by monocytic cells. Here, we show in mice and in human cells that, in the absence of any inflammatory challenge, TET2 downregulation promotes the production of MIF (macrophage migration inhibitory factor), a pivotal mediator of atherosclerotic lesion formation. In healthy monocytes, TET2 is recruited to MIF promoter and interacts with the transcription factor EGR1 and histone deacetylases. Disruption of these interactions as a consequence of TET2-decreased expression favors EGR1-driven transcription of MIF gene and its secretion. MIF favors monocytic differentiation of myeloid progenitors. These results designate MIF as a chronically overproduced chemokine and a potential therapeutic target in patients with clonal TET2 downregulation in myeloid cells. To improve our understanding of the pathological role of TET2 mutations, Pronier, Imanci et al. use mice and human cells to show that TET2 downregulation promotes the production of macrophage migration inhibitory factor (MIF). In addition they show that whilst TET2 is recruited to the MIF promoter in healthy monocytes, decreased TET2 expression results in chronic overproduction of MIF - suggesting that MIF signaling could therefore constitute a potential therapeutic target for conditions associated with TET2 mutations.
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Affiliation(s)
- Elodie Pronier
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Owkin Lab, Owkin, Inc., New York, NY, 10003, USA
| | - Aygun Imanci
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France
| | - Dorothée Selimoglu-Buet
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France
| | - Bouchra Badaoui
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Département d'Hématologie et Immunologie Biologiques, 94000, Créteil, France
| | - Raphael Itzykson
- AP-HP, Service Hématologie Adultes, Hôpital Saint-Louis, 75010, Paris, France
| | - Thierry Roger
- Infectious Disease Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1011, Lausanne, Switzerland
| | - Chloé Jego
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France
| | - Audrey Naimo
- INSERM US23, CNRS UMS 3655, AMMICa, Genomic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Maëla Francillette
- INSERM US23, CNRS UMS 3655, AMMICa, Genomic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Marie Breckler
- INSERM US23, CNRS UMS 3655, AMMICa, Genomic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Orianne Wagner-Ballon
- AP-HP, Hôpitaux Universitaires Henri-Mondor, Département d'Hématologie et Immunologie Biologiques, 94000, Créteil, France.,Université Paris Est Créteil, INSERM, IMRB, Equipe 9, 94010, Créteil, France
| | - Maria E Figueroa
- Human Genetics, University of Miami Miller School of Medicine, 33136, Miami, USA.,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 33136, Miami, USA
| | - Marine Aglave
- INSERM US23, CNRS UMS 3655, AMMICa, Bioinformatic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Daniel Gautheret
- INSERM US23, CNRS UMS 3655, AMMICa, Bioinformatic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Françoise Porteu
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France
| | - Olivier A Bernard
- Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France.,INSERM U1170, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - William Vainchenker
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France
| | - François Delhommeau
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, 75012, Paris, France.,AP-HP, Sorbonne Université, Hôpital Saint-Antoine, Service d'Hématologie et Immunologie Biologique, 75012, Paris, France
| | - Eric Solary
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France.,Hematology department, Gustave Roussy Cancer Center, 94805, Villejuif, France
| | - Nathalie M Droin
- INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France. .,Université Paris Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France. .,INSERM US23, CNRS UMS 3655, AMMICa, Genomic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France.
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18
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Coker SJ, Smith-Díaz CC, Dyson RM, Vissers MCM, Berry MJ. The Epigenetic Role of Vitamin C in Neurodevelopment. Int J Mol Sci 2022; 23:ijms23031208. [PMID: 35163133 PMCID: PMC8836017 DOI: 10.3390/ijms23031208] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/16/2022] [Accepted: 01/17/2022] [Indexed: 02/07/2023] Open
Abstract
The maternal diet during pregnancy is a key determinant of offspring health. Early studies have linked poor maternal nutrition during gestation with a propensity for the development of chronic conditions in offspring. These conditions include cardiovascular disease, type 2 diabetes and even compromised mental health. While multiple factors may contribute to these outcomes, disturbed epigenetic programming during early development is one potential biological mechanism. The epigenome is programmed primarily in utero, and during this time, the developing fetus is highly susceptible to environmental factors such as nutritional insults. During neurodevelopment, epigenetic programming coordinates the formation of primitive central nervous system structures, neurogenesis, and neuroplasticity. Dysregulated epigenetic programming has been implicated in the aetiology of several neurodevelopmental disorders such as Tatton-Brown-Rahman syndrome. Accordingly, there is great interest in determining how maternal nutrient availability in pregnancy might affect the epigenetic status of offspring, and how such influences may present phenotypically. In recent years, a number of epigenetic enzymes that are active during embryonic development have been found to require vitamin C as a cofactor. These enzymes include the ten-eleven translocation methylcytosine dioxygenases (TETs) and the Jumonji C domain-containing histone lysine demethylases that catalyse the oxidative removal of methyl groups on cytosines and histone lysine residues, respectively. These enzymes are integral to epigenetic regulation and have fundamental roles in cellular differentiation, the maintenance of pluripotency and development. The dependence of these enzymes on vitamin C for optimal catalytic activity illustrates a potentially critical contribution of the nutrient during mammalian development. These insights also highlight a potential risk associated with vitamin C insufficiency during pregnancy. The link between vitamin C insufficiency and development is particularly apparent in the context of neurodevelopment and high vitamin C concentrations in the brain are indicative of important functional requirements in this organ. Accordingly, this review considers the evidence for the potential impact of maternal vitamin C status on neurodevelopmental epigenetics.
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Affiliation(s)
- Sharna J. Coker
- Perinatal & Developmental Physiology Group, Department of Paediatrics & Child Health, University of Otago, Wellington 6242, New Zealand; (S.J.C.); (R.M.D.)
| | - Carlos C. Smith-Díaz
- Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand;
| | - Rebecca M. Dyson
- Perinatal & Developmental Physiology Group, Department of Paediatrics & Child Health, University of Otago, Wellington 6242, New Zealand; (S.J.C.); (R.M.D.)
| | - Margreet C. M. Vissers
- Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand;
- Correspondence: (M.C.M.V.); (M.J.B.)
| | - Mary J. Berry
- Perinatal & Developmental Physiology Group, Department of Paediatrics & Child Health, University of Otago, Wellington 6242, New Zealand; (S.J.C.); (R.M.D.)
- Correspondence: (M.C.M.V.); (M.J.B.)
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19
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Dusadeemeelap C, Rojasawasthien T, Matsubara T, Kokabu S, Addison WN. Inhibition of TET-mediated DNA demethylation suppresses osteoblast differentiation. FASEB J 2022; 36:e22153. [PMID: 34997955 DOI: 10.1096/fj.202101402r] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 12/10/2021] [Accepted: 12/23/2021] [Indexed: 12/26/2022]
Abstract
DNA methylation is an epigenetic modification critical for the regulation of chromatin structure and gene expression during development and disease. The ten-eleven translocation (TET) enzyme family catalyzes the hydroxymethylation and subsequent demethylation of DNA by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Little is known about TET protein function due to a lack of pharmacological tools to manipulate DNA hydroxymethylation levels. In this study, we examined the role of TET-mediated DNA hydroxymethylation during BMP-induced C2C12 osteoblast differentiation using a novel cytosine-based selective TET enzyme inhibitor, Bobcat339 (BC339). Treatment of C2C12 cells with BC339 increased global 5mC and decreased global 5hmC without adversely affecting cell viability, proliferation, or apoptosis. Furthermore, BC339 treatment inhibited osteoblast marker gene expression and decreased alkaline phosphatase activity during differentiation. Methylated DNA immunoprecipitation and bisulfite sequencing showed that inhibition of TET with BC339 led to increased 5mC at specific CpG-rich regions at the promoter of Sp7, a key osteoblast transcription factor. Consistent with promoter 5mC marks being associated with transcriptional repression, luciferase activity of an Sp7-promoter-reporter construct was repressed by in vitro DNA methylation or BC339. Chromatin immunoprecipitation analysis confirmed that TET2 does indeed occupy the promoter region of Sp7. Accordingly, forced overexpression of SP7 rescued the inhibition of osteogenic differentiation by BC339. In conclusion, our data suggest that TET-mediated DNA demethylation of genomic regions, including the Sp7 promoter, plays a role in the initiation of osteoblast differentiation. Furthermore, BC339 is a novel pharmacological tool for the modulation of DNA methylation dynamics for research and therapeutic applications.
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Affiliation(s)
- Chirada Dusadeemeelap
- Division of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu, Japan.,Division of Special Needs and Geriatric Dentistry, Kyushu Dental University, Kitakyushu, Japan
| | - Thira Rojasawasthien
- Division of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu, Japan
| | - Takuma Matsubara
- Division of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu, Japan
| | - Shoichiro Kokabu
- Division of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu, Japan
| | - William N Addison
- Division of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu, Japan
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20
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Li Q, Chen J, Liang F, Zhang J, Qu W, Huang X, Cheng X, Zhao X, Yang Z, Xu S, Li X. RYBP modulates embryonic neurogenesis involving the Notch signaling pathway in a PRC1-independent pattern. Stem Cell Reports 2021; 16:2988-3004. [PMID: 34798064 PMCID: PMC8693662 DOI: 10.1016/j.stemcr.2021.10.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 11/26/2022] Open
Abstract
RYBP (Ring1 and YY1 binding protein), an essential component of the Polycomb repressive complex 1 (PRC1), plays pivotal roles in development and diseases. However, the roles of Rybp in neuronal development remains completely unknown. In the present study, we have shown that the depletion of Rybp inhibits proliferation and promotes neuronal differentiation of embryonic neural progenitor cells (eNPCs). In addition, Rybp deficiency impairs the morphological development of neurons. Mechanistically, Rybp deficiency does not affect the global level of ubiquitination of H2A, but it inhibits Notch signaling pathway in eNPCs. The direct interaction between RYBP and CIR1 facilitates the binding of RBPJ to Notch intracellular domain (NICD) and consequently activated Notch signaling. Rybp loss promotes CIR1 competing with RBPJ to bind with NICD, and inhibits Notch signaling. Furthermore, ectopic Hes5, Notch signaling downstream target, rescues Rybp-deficiency-induced deficits. Collectively, our findings show that RYBP regulates embryonic neurogenesis and neuronal development through modulating Notch signaling in a PRC1-independent manner.
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Affiliation(s)
- Qian Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Junchen Chen
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Feng Liang
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310002, China
| | - Jinyu Zhang
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Wenzheng Qu
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xiaoli Huang
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xuejun Cheng
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xingsen Zhao
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Zhanjun Yang
- Department of Human Anatomy, Baotou Medical College, Baotou, 014040, China
| | - Shunliang Xu
- Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China.
| | - Xuekun Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310029, China.
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21
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Ji J, You Q, Zhang J, Wang Y, Cheng J, Huang X, Zhang Y. Downregulation of TET1 Promotes Glioma Cell Proliferation and Invasion by Targeting Wnt/ β-Catenin Pathway. Anal Cell Pathol (Amst) 2021; 2021:8980711. [PMID: 34926132 PMCID: PMC8677395 DOI: 10.1155/2021/8980711] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/19/2021] [Indexed: 11/17/2022] Open
Abstract
Glioma is the most common malignant tumor in adult brain characteristic with poor prognosis and low survival rate. Despite the application of advanced surgery, chemotherapy, and radiotherapy, the patients with glioma suffer poor treatment effects due to the complex molecular mechanisms of pathological process. In this paper, we conducted the experiments to prove the critical roles TET1 played in glioma and explored the downstream targets of TET1 in order to provide a novel theoretical basis for clinical glioma therapy. RT-qPCR was adopted to detect the RNA level of TET1 and β-catenin; Western blot was taken to determine the expression of proteins. CCK8 assay was used to detect the proliferation of glioma cells. Flow cytometry was used to test cell apoptosis and distribution of cell cycle. To detect the migration and invasion of glioma cells, wound healing assay and Transwell were performed. It was found that downregulation of TET1 could promote the proliferation migration and invasion of glioma cells and the concomitant upregulation of β-catenin, and its downstream targets like cyclinD1 and c-myc were observed. The further rescue experiments were performed, wherein downregulation of β-catenin markedly decreases glioma cell proliferation in vitro and in vivo. This study confirmed the tumor suppressive function of TET1 and illustrated the underlying molecular mechanisms regulated by TET1 in glioma.
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Affiliation(s)
- Jianwen Ji
- Department of Neurological Center, The Third Affiliated Hospital of Chongqing Medical University (General Hospital), Chongqing 401120, China
| | - Qiuxiang You
- Department of Neurological Center, The Third Affiliated Hospital of Chongqing Medical University (General Hospital), Chongqing 401120, China
| | - Jidong Zhang
- Department of Neurological Center, The Third Affiliated Hospital of Chongqing Medical University (General Hospital), Chongqing 401120, China
| | - Yutao Wang
- Department of Neurological Center, The Third Affiliated Hospital of Chongqing Medical University (General Hospital), Chongqing 401120, China
| | - Jing Cheng
- Department of Neurological Center, The Third Affiliated Hospital of Chongqing Medical University (General Hospital), Chongqing 401120, China
| | - Xiangyun Huang
- Department of Neurological Center, The Third Affiliated Hospital of Chongqing Medical University (General Hospital), Chongqing 401120, China
| | - Yundong Zhang
- Department of Neurological Center, The Third Affiliated Hospital of Chongqing Medical University (General Hospital), Chongqing 401120, China
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22
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Xu W, Zhang X, Liang F, Cao Y, Li Z, Qu W, Zhang J, Bi Y, Sun C, Zhang J, Sun B, Shu Q, Li X. Tet1 Regulates Astrocyte Development and Cognition of Mice Through Modulating GluA1. Front Cell Dev Biol 2021; 9:644375. [PMID: 34778243 PMCID: PMC8581465 DOI: 10.3389/fcell.2021.644375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open
Abstract
Tet (Ten eleven translocation) family proteins-mediated 5-hydroxymethylcytosine (5hmC) is highly enriched in the neuronal system, and is involved in diverse biological processes and diseases. However, the function of 5hmC in astrocyte remains completely unknown. In the present study, we show that Tet1 deficiency alters astrocyte morphology and impairs neuronal function. Specific deletion of Tet1 in astrocyte impairs learning and memory ability of mice. Using 5hmC high-throughput DNA sequencing and RNA sequencing, we present the distribution of 5hmC among genomic features in astrocyte and show that Tet1 deficiency induces differentially hydroxymethylated regions (DhMRs) and alters gene expression. Mechanistically, we found that Tet1 deficiency leads to the abnormal Ca2+ signaling by regulating the expression of GluA1, which can be rescued by ectopic GluA1. Collectively, our findings suggest that Tet1 plays important function in astrocyte physiology by regulating Ca2+ signaling.
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Affiliation(s)
- Weize Xu
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Child Health, Hangzhou, China
| | - Xicheng Zhang
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Child Health, Hangzhou, China
| | - Feng Liang
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yuhang Cao
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Child Health, Hangzhou, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ziyi Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Wenzheng Qu
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Child Health, Hangzhou, China
| | - Jinyu Zhang
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Child Health, Hangzhou, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yanhua Bi
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chongran Sun
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianmin Zhang
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Binggui Sun
- Department of Neurobiology and Department of Neurology of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiang Shu
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Child Health, Hangzhou, China
| | - Xuekun Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Child Health, Hangzhou, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, China
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23
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Gillotin S, Sahni V, Lepko T, Hanspal MA, Swartz JE, Alexopoulou Z, Marshall FH. Targeting impaired adult hippocampal neurogenesis in ageing by leveraging intrinsic mechanisms regulating Neural Stem Cell activity. Ageing Res Rev 2021; 71:101447. [PMID: 34403830 DOI: 10.1016/j.arr.2021.101447] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/14/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023]
Abstract
Deficits in adult neurogenesis may contribute to the aetiology of many neurodevelopmental, psychiatric and neurodegenerative diseases. Genetic ablation of neurogenesis provides proof of concept that adult neurogenesis is required to sustain complex and dynamic cognitive functions, such as learning and memory, mostly by providing a high degree of plasticity to neuronal circuits. In addition, adult neurogenesis is reactive to external stimuli and the environment making it particularly susceptible to impairment and consequently contributing to comorbidity. In the human brain, the dentate gyrus of the hippocampus is the main active source of neural stem cells that generate granule neurons throughout life. The regulation and preservation of the pool of neural stem cells is central to ensure continuous and healthy adult hippocampal neurogenesis (AHN). Recent advances in genetic and metabolic profiling alongside development of more predictive animal models have contributed to the development of new concepts and the emergence of molecular mechanisms that could pave the way to the implementation of new therapeutic strategies to treat neurological diseases. In this review, we discuss emerging molecular mechanisms underlying AHN that could be embraced in drug discovery to generate novel concepts and targets to treat diseases of ageing including neurodegeneration. To support this, we review cellular and molecular mechanisms that have recently been identified to assess how AHN is sustained throughout life and how AHN is associated with diseases. We also provide an outlook on strategies for developing correlated biomarkers that may accelerate the translation of pre-clinical and clinical data and review clinical trials for which modulation of AHN is part of the therapeutic strategy.
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24
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Qu W, Zhuang Y, Li X. The roles of epigenetic modifications in neurodegenerative diseases. Zhejiang Da Xue Xue Bao Yi Xue Ban 2021; 50:642-650. [PMID: 34986527 PMCID: PMC8732261 DOI: 10.3724/zdxbyxb-2021-0160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/30/2021] [Indexed: 06/14/2023]
Abstract
In neuronal system, epigenetic modifications are essential for neuronal development, the fate determination of neural stem cells and neuronal function. The dysfunction of epigenetic regulation is closely related to occurrence and development of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease. Abnormally elevated DNA methylation inhibits the expression of some DNA repair-related genes and affects the progression of Huntington's disease. In the brain of Alzheimer's disease patients, the levels of H3K27ac and H3K9ac histone modifications increased. In addition, the alteration of RNA methylation in animal models of Alzheimer's disease and Parkinson's disease showed discrepancy trends. Therefore, epigenetic modifications may serve as potential therapeutic targets for neurodegenerative diseases. Here, we summarize the recent progress of the roles of epigenetic modifications in neurodegenerative diseases.
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Affiliation(s)
- Wenzheng Qu
- of Translational Medicine, Zhejiang University, Hangzhou 310029, China
| | - Yingliang Zhuang
- of Translational Medicine, Zhejiang University, Hangzhou 310029, China
| | - Xuekun Li
- of Translational Medicine, Zhejiang University, Hangzhou 310029, China
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25
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Wang W, Zhao X, Shao Y, Duan X, Wang Y, Li J, Li J, Li D, Li X, Wong J. Mutation-induced DNMT1 cleavage drives neurodegenerative disease. SCIENCE ADVANCES 2021; 7:eabe8511. [PMID: 34516921 PMCID: PMC8442919 DOI: 10.1126/sciadv.abe8511] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 07/12/2021] [Indexed: 06/13/2023]
Abstract
Specific mutations within the replication foci targeting sequence (RFTS) domain of human DNMT1 are causative of two types of adult-onset neurodegenerative diseases, HSAN1E and ADCA-DN, but the underlying mechanisms are largely unknown. We generated Dnmt1-M1 and Dnmt1-M2 knock-in mouse models that are equivalent to Y495C and D490E-P491Y mutation in patients with HSAN1E, respectively. We found that both mutant heterozygous mice are viable, have reduced DNMT1 proteins, and exhibit neurodegenerative phenotypes including impaired learning and memory. The homozygous mutants die around embryonic day 10.5 and are apparently devoid of DNMT1 proteins. We present the evidence that the mutant DNMT1 proteins are unstable, most likely because of cleavage within RFTS domain by an unidentified proteinase. Moreover, we provide evidence that the RFTS mutation–induced cleavage of DNMT1, but not mutation itself, is responsible for functional defect of mutant DNMT1. Our study shed light on the mechanism of DNMT1 RFTS mutation causing neurodegenerative diseases.
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Affiliation(s)
- Wencai Wang
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital–ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
- Joint Center for Translational Medicine, Fengxian District Central Hospital, 6600th Nanfeng Road, Fengxian District, Shanghai 201499, China
| | - Xingsen Zhao
- The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China
- Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
- National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Yanjiao Shao
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital–ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Xiaoya Duan
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital–ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Yaling Wang
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital–ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jialun Li
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital–ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jiwen Li
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital–ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Dali Li
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital–ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Xuekun Li
- The Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China
- Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
- National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Jiemin Wong
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital–ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
- Joint Center for Translational Medicine, Fengxian District Central Hospital, 6600th Nanfeng Road, Fengxian District, Shanghai 201499, China
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26
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Gao H, Cheng X, Chen J, Ji C, Guo H, Qu W, Dong X, Chen Y, Ma L, Shu Q, Li X. Fto-modulated lipid niche regulates adult neurogenesis through modulating adenosine metabolism. Hum Mol Genet 2021; 29:2775-2787. [PMID: 32766784 DOI: 10.1093/hmg/ddaa171] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/01/2020] [Accepted: 07/01/2020] [Indexed: 12/16/2022] Open
Abstract
Adult neurogenesis is regulated by diverse factors including the local environment, i.e. the neurogenic niche. However, whether the lipid in the brain regulates adult neurogenesis and related mechanisms remains largely unknown. In the present study, we found that lipid accumulates in the brain during postnatal neuronal development. Conditional knockout of Fto (cKO) in lipid not only reduced the level of lipid in the brain but also impaired the learning and memory of mice. In addition, Fto deficiency in lipid did not affect the proliferation of adult neural stem cells (aNSCs), but it did inhibit adult neurogenesis by inducing cell apoptosis. Mechanistically, specific deleting Fto in lipid altered gene expression and increased adenosine secretion of adipocytes. The treatment of adenosine promoted the apoptosis of newborn neurons. As a whole, these results reveal the important function of the lipid niche and its associated mechanism in regulating adult neurogenesis.
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Affiliation(s)
- Hui Gao
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China.,National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xuejun Cheng
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.,National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Junchen Chen
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Chai Ji
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.,National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Hongfeng Guo
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Wenzheng Qu
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.,National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xiaoxue Dong
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.,National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Yingyan Chen
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Linghan Ma
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Qiang Shu
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.,National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xuekun Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China.,National Clinical Research Center for Child Health, Hangzhou 310052, China
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27
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Ten-eleven translocation 1 mediated-DNA hydroxymethylation is required for myelination and remyelination in the mouse brain. Nat Commun 2021; 12:5091. [PMID: 34429415 PMCID: PMC8385008 DOI: 10.1038/s41467-021-25353-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 08/05/2021] [Indexed: 11/08/2022] Open
Abstract
Ten-eleven translocation (TET) proteins, the dioxygenase for DNA hydroxymethylation, are important players in nervous system development and diseases. However, their role in myelination and remyelination after injury remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during differentiation of oligodendrocyte-progenitor cells (OPC). Ablation of Tet1 results in stage-dependent defects in oligodendrocyte (OL) development and myelination in the mouse brain. The mice lacking Tet1 in the oligodendrocyte lineage develop behavioral deficiency. We also show that TET1 is required for remyelination in adulthood. Transcriptomic, genomic occupancy, and 5-hydroxymethylcytosine (5hmC) profiling reveal a critical TET1-regulated epigenetic program for oligodendrocyte differentiation that includes genes associated with myelination, cell division, and calcium transport. Tet1-deficient OPCs exhibit reduced calcium activity, increasing calcium activity rescues the differentiation defects in vitro. Deletion of a TET1-5hmC target gene, Itpr2, impairs the onset of OPC differentiation. Together, our results suggest that stage-specific TET1-mediated epigenetic programming and intracellular signaling are important for proper myelination and remyelination in mice.
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28
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Li L, Qiu Y, Miao M, Liu Z, Li W, Zhu Y, Wang Q. Reduction of Tet2 exacerbates early stage Alzheimer's pathology and cognitive impairments in 2×Tg-AD mice. Hum Mol Genet 2021; 29:1833-1852. [PMID: 31943063 DOI: 10.1093/hmg/ddz282] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 10/20/2019] [Accepted: 11/19/2019] [Indexed: 12/29/2022] Open
Abstract
Abnormal modification of 5-hydroxymethylcytosine (5hmC) is closely related to the occurrence of Alzheimer's disease (AD). However, the role of 5hmC and its writers, ten-eleven translocation (Tet) proteins, in regulating the pathogenesis of AD remains largely unknown. We detected a significant decrease in 5hmC and Tet2 levels in the hippocampus of aged APPswe/PSEN1 double-transgenic (2×Tg-AD) mice that coincides with abundant amyloid-β (Aβ) plaque accumulation. On this basis, we examined the reduction of Tet2 expression in the hippocampus at early disease stages, which caused a decline of 5hmC levels and led young 2×Tg-AD mice to present with advanced stages of AD-related pathological hallmarks, including Aβ accumulation, GFAP-positive astrogliosis and Iba1-positive microglia overgrowth as well as the overproduction of pro-inflammatory factors. Additionally, the loss of Tet2 in the 2×Tg-AD mice at 5 months of age accelerated hippocampal-dependent learning and memory impairments compared to age-matched control 2×Tg-AD mice. In contrast, restoring Tet2 expression in adult neural stem cells isolated from aged 2×Tg-AD mice hippocampi increased 5hmC levels and increased their regenerative capacity, suggesting that Tet2 might be an exciting target for rejuvenating the brain during aging and AD. Further, hippocampal RNA sequencing data revealed that the expression of altered genes identified in both Tet2 knockdown and control 2×Tg-AD mice was significantly associated with inflammation response. Finally, we demonstrated that Tet2-mediated 5hmC epigenetic modifications regulate AD pathology by interacting with HDAC1. These results suggest a combined approach for the regulation and treatment of AD-related memory impairment and cognitive symptoms by increasing Tet2 via HDAC1 suppression.
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Affiliation(s)
- Liping Li
- Ningbo Key Laboratory of Behavioral Neuroscience, Department of Physiology and Pharmacology, Ningbo University School of Medicine, Ningbo 315211, China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo 315211, China
| | - Yisha Qiu
- Ningbo Key Laboratory of Behavioral Neuroscience, Department of Physiology and Pharmacology, Ningbo University School of Medicine, Ningbo 315211, China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo 315211, China
| | - Miao Miao
- Ningbo Key Laboratory of Behavioral Neuroscience, Department of Physiology and Pharmacology, Ningbo University School of Medicine, Ningbo 315211, China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo 315211, China
| | - Zhitao Liu
- Faculty of Sports Science, Ningbo University, Ningbo 315211, China
| | - Wanyi Li
- Faculty of Sports Science, Ningbo University, Ningbo 315211, China
| | - Yiyi Zhu
- Ningbo Key Laboratory of Behavioral Neuroscience, Department of Physiology and Pharmacology, Ningbo University School of Medicine, Ningbo 315211, China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo 315211, China
| | - Qinwen Wang
- Ningbo Key Laboratory of Behavioral Neuroscience, Department of Physiology and Pharmacology, Ningbo University School of Medicine, Ningbo 315211, China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo 315211, China
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29
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Cao Y, Zhuang Y, Chen J, Xu W, Shou Y, Huang X, Shu Q, Li X. Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice. Hum Mol Genet 2021; 29:727-735. [PMID: 31751468 DOI: 10.1093/hmg/ddz274] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 10/13/2019] [Accepted: 11/04/2019] [Indexed: 12/17/2022] Open
Abstract
N 6-methyladenosine (m6A) modification of RNA is deposited by the methyltransferase complex consisting of Mettl3 and Mettl14 and erased by demethylase Fto and Alkbh5 and is involved in diverse biological processes. However, it remains largely unknown the specific function and mechanism of Fto in regulating adult neural stem cells (aNSCs). In the present study, utilizing a conditional knockout (cKO) mouse model, we show that the specific ablation of Fto in aNSCs transiently increases the proliferation of aNSCs and promotes neuronal differentiation both in vitro and in vivo, but in a long term, the specific ablation of Fto inhibits adult neurogenesis and neuronal development. Mechanistically, Fto deficiency results in a significant increase in m6A modification in Pdgfra and Socs5. The increased expression of Pdgfra and decreased expression of Socs5 synergistically promote the phosphorylation of Stat3. The modulation of Pdgfra and Socs5 can rescue the neurogenic deficits induced by Fto depletion. Our results together reveal an important function of Fto in regulating aNSCs through modulating Pdgfra/Socs5-Stat3 pathway.
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Affiliation(s)
- Yuhang Cao
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310051, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China.,National Clinical Research Center for Child Health, 3333 Binsheng Road, Hangzhou, Zhejiang 310051, China
| | - Yingliang Zhuang
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310051, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China.,National Clinical Research Center for Child Health, 3333 Binsheng Road, Hangzhou, Zhejiang 310051, China
| | - Junchen Chen
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310051, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China.,National Clinical Research Center for Child Health, 3333 Binsheng Road, Hangzhou, Zhejiang 310051, China
| | - Weize Xu
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310051, China.,National Clinical Research Center for Child Health, 3333 Binsheng Road, Hangzhou, Zhejiang 310051, China
| | - Yikai Shou
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310051, China.,National Clinical Research Center for Child Health, 3333 Binsheng Road, Hangzhou, Zhejiang 310051, China
| | - Xiaoli Huang
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310051, China.,National Clinical Research Center for Child Health, 3333 Binsheng Road, Hangzhou, Zhejiang 310051, China
| | - Qiang Shu
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310051, China.,National Clinical Research Center for Child Health, 3333 Binsheng Road, Hangzhou, Zhejiang 310051, China
| | - Xuekun Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310051, China.,The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China.,National Clinical Research Center for Child Health, 3333 Binsheng Road, Hangzhou, Zhejiang 310051, China
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30
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Zhang Q, Hu Q, Wang J, Miao Z, Li Z, Zhao Y, Wan B, Allen EG, Sun M, Jin P, Xu X. Stress modulates Ahi1-dependent nuclear localization of Ten-Eleven Translocation Protein 2. Hum Mol Genet 2021; 30:2149-2160. [PMID: 34218273 DOI: 10.1093/hmg/ddab179] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/08/2021] [Accepted: 06/24/2021] [Indexed: 11/13/2022] Open
Abstract
Major depression disorder (MDD) is one of the most common psychiatric diseases. Recent evidence supports that environmental stress affects gene expression and promotes the pathological process of depression through epigenetic mechanisms. Three Ten-Eleven Translocation (Tet) enzymes are epigenetic regulators of gene expression that promote 5-hydroxymethylcytosine (5hmC) modification of genes. Here, we show that the loss of Tet2 can induce depression-like phenotypes in mice. Paradoxically, using the paradigms of chronic stress, such as chronic mild stress (CMS) and chronic social defeat stress (CSDS), we found that depressive behaviors were associated with increased Tet2 expression but decreased global 5hmC level in hippocampus. We examined the genome-wide 5hmC profile in the hippocampus of Tet2 knockout mice and identified 651 dynamically hydroxymethylated regions, some of which overlapped with known depression-associated loci. We further showed that chronic stress could induce the abnormal nuclear translocation of Tet2 protein from cytosol. Through Tet2 immunoprecipitation and mass spectrum analyses, we identified a cellular trafficking protein, Abelson helper integration site-1 (Ahi1), which could interact with Tet2 protein. Ahi1 knockout or knockdown caused the accumulation of Tet2 in cytosol. The reduction of Ahi1 protein under chronic stress explained the abnormal Ahi1-dependent nuclear translocation of Tet2. These findings together provide the evidence for a critical role of modulating Tet2 nuclear translocation in regulating stress response.
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Affiliation(s)
- Qian Zhang
- Departments of Neurology, the First Affiliated Hospital of Soochow University, Suzhou City, China.,Institute of Neuroscience, Soochow University, Suzhou City, China
| | - Qicheng Hu
- Institute of Neuroscience, Soochow University, Suzhou City, China
| | - Junjie Wang
- Institute of Neuroscience, Soochow University, Suzhou City, China
| | - Zhigang Miao
- Institute of Neuroscience, Soochow University, Suzhou City, China
| | - Ziyi Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yuwen Zhao
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Bo Wan
- Institute of Neuroscience, Soochow University, Suzhou City, China
| | - Emily G Allen
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Miao Sun
- The Institute of Fetology, the First Affiliated Hospital of Soochow University, Suzhou City, China
| | - Peng Jin
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Xingshun Xu
- Departments of Neurology, the First Affiliated Hospital of Soochow University, Suzhou City, China.,Institute of Neuroscience, Soochow University, Suzhou City, China.,Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu, China
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31
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Meng C, Gu L, Li Y, Li R, Cao Y, Li Z, Allen EG, Zhu D, Jin P. Ten-eleven translocation 2 modulates allergic inflammation by 5-hydroxymethylcytosine remodeling of immunologic pathways. Hum Mol Genet 2021; 30:1985-1995. [PMID: 34165552 DOI: 10.1093/hmg/ddab167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 02/02/2023] Open
Abstract
Allergic rhinitis (AR) is an allergen specific IgE-mediated inflammatory disease. Both genetic and environmental factors could play a role in the pathophysiology of AR. 5-methylcytosine (5-mC) can be converted to 5-hydroxymethylcytosine (5hmC) by the Ten-Eleven Translocation (TET) family of proteins as part of active DNA de-methylation pathway. 5hmC plays an important role in regulation of gene expression and differentiation in immune cells. Here we show that loss of ten-eleven translocation protein 2 (Tet2) could impact the severity of AR in the ovalbumin-induced mouse model. Genome-wide 5hmC profiling of both wildtype and Tet2 KO mice in response to AR revealed that the loss of Tet2 could lead to 5hmC alteration at specific immune response genes. Both partial loss and complete loss of Tet2 alters the 5hmC dynamic remodeling for the adaptive immune pathway, as well as cytokines. Thus, our results reveal a new role of Tet2 in immunology, and Tet2 may serve as a promising target in regulating the level of immune response.
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Affiliation(s)
- Cuida Meng
- Department of Otolaryngology Head and Neck Surgery, China-Japan Union of Jilin University, Changchun, China.,Jilin provincial Key Laboratory of Precise Diagnosis and Treatment of Upper Airway Allergic Diseases, China
| | - Lei Gu
- Affiliated First hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yujing Li
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Ronghua Li
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Yiqu Cao
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Ziyi Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030
| | - Emily G Allen
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Dongdong Zhu
- Department of Otolaryngology Head and Neck Surgery, China-Japan Union of Jilin University, Changchun, China.,Jilin provincial Key Laboratory of Precise Diagnosis and Treatment of Upper Airway Allergic Diseases, China
| | - Peng Jin
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
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32
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Dick A, Chen A. The role of TET proteins in stress-induced neuroepigenetic and behavioural adaptations. Neurobiol Stress 2021; 15:100352. [PMID: 34189192 PMCID: PMC8220100 DOI: 10.1016/j.ynstr.2021.100352] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 05/21/2021] [Accepted: 06/05/2021] [Indexed: 12/27/2022] Open
Abstract
Over the past decade, critical, non-redundant roles of the ten-eleven translocation (TET) family of dioxygenase enzymes have been identified in the brain during developmental and postnatal stages. Specifically, TET-mediated active demethylation, involving the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and subsequent oxidative derivatives, is dynamically regulated in response to environmental stimuli such as neuronal activity, learning and memory processes, and stressor exposure. Such changes may therefore perpetuate stable and dynamic transcriptional patterns within neuronal populations required for neuroplasticity and behavioural adaptation. In this review, we will highlight recent evidence supporting a role of TET protein function and active demethylation in stress-induced neuroepigenetic and behavioural adaptations. We further explore potential mechanisms by which TET proteins may mediate both the basal and pathological embedding of stressful life experiences within the brain of relevance to stress-related psychiatric disorders.
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Affiliation(s)
- Alec Dick
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
- Corresponding author.
| | - Alon Chen
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany
- The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
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33
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Kuehner JN, Chen J, Bruggeman EC, Wang F, Li Y, Xu C, McEachin ZT, Li Z, Chen L, Hales CM, Wen Z, Yang J, Yao B. 5-hydroxymethylcytosine is dynamically regulated during forebrain organoid development and aberrantly altered in Alzheimer's disease. Cell Rep 2021; 35:109042. [PMID: 33910000 PMCID: PMC8106871 DOI: 10.1016/j.celrep.2021.109042] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 02/02/2021] [Accepted: 04/06/2021] [Indexed: 12/21/2022] Open
Abstract
5-hydroxymethylcytosine (5hmC) undergoes dynamic changes during mammalian brain development, and its dysregulation is associated with Alzheimer’s disease (AD). The dynamics of 5hmC during early human brain development and how they contribute to AD pathologies remain largely unexplored. We generate 5hmC and transcriptome profiles encompassing several developmental time points of healthy forebrain organoids and organoids derived from several familial AD patients. Stage-specific differentially hydroxymethylated regions demonstrate an acquisition or depletion of 5hmC modifications across developmental stages. Additionally, genes concomitantly increasing or decreasing in 5hmC and gene expression are enriched in neurobiological or early developmental processes, respectively. Importantly, our AD organoids corroborate cellular and molecular phenotypes previously observed in human AD brains. 5hmC is significantly altered in developmentally programmed 5hmC intragenic regions in defined fetal histone marks and enhancers in AD organoids. These data suggest a highly coordinated molecular system that may be dysregulated in these early developing AD organoids. Kuehner et al. use forebrain organoids derived from healthy controls to study the dynamics of 5hmC across early brain development. In addition, organoids derived from several AD patients reveal aberrant 5hmC patterns that could disrupt early neuronal networks and contribute to the onset of AD later in life.
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Affiliation(s)
- Janise N Kuehner
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Junyu Chen
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Emily C Bruggeman
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Feng Wang
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Yangping Li
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Chongchong Xu
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA; Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Zachary T McEachin
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA
| | - Ziyi Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Li Chen
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chadwick M Hales
- Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Zhexing Wen
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA; Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
| | - Jingjing Yang
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
| | - Bing Yao
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
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34
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Sun J, Yang J, Miao X, Loh HH, Pei D, Zheng H. Proteins in DNA methylation and their role in neural stem cell proliferation and differentiation. CELL REGENERATION (LONDON, ENGLAND) 2021; 10:7. [PMID: 33649938 PMCID: PMC7921253 DOI: 10.1186/s13619-020-00070-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 11/25/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Epigenetic modifications, namely non-coding RNAs, DNA methylation, and histone modifications such as methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation play a significant role in brain development. DNA methyltransferases, methyl-CpG binding proteins, and ten-eleven translocation proteins facilitate the maintenance, interpretation, and removal of DNA methylation, respectively. Different forms of methylation, including 5-methylcytosine, 5-hydroxymethylcytosine, and other oxidized forms, have been detected by recently developed sequencing technologies. Emerging evidence suggests that the diversity of DNA methylation patterns in the brain plays a key role in fine-tuning and coordinating gene expression in the development, plasticity, and disorders of the mammalian central nervous system. Neural stem cells (NSCs), originating from the neuroepithelium, generate neurons and glial cells in the central nervous system and contribute to brain plasticity in the adult mammalian brain. MAIN BODY Here, we summarized recent research in proteins responsible for the establishment, maintenance, interpretation, and removal of DNA methylation and those involved in the regulation of the proliferation and differentiation of NSCs. In addition, we discussed the interactions of chemicals with epigenetic pathways to regulate NSCs as well as the connections between proteins involved in DNA methylation and human diseases. CONCLUSION Understanding the interplay between DNA methylation and NSCs in a broad biological context can facilitate the related studies and reduce potential misunderstanding.
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Affiliation(s)
- Jiaqi Sun
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China.
| | - Junzheng Yang
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China
| | - Xiaoli Miao
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China
| | - Horace H Loh
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China
| | - Duanqing Pei
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China.,CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, 510530, China.,Institutes for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,School of Life Science, Westlake University, Hangzhou, 310024, China
| | - Hui Zheng
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou, 510700, China. .,CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. .,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, 510530, China. .,Institutes for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
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35
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Chen J, Dong X, Cheng X, Zhu Q, Zhang J, Li Q, Huang X, Wang M, Li L, Guo W, Sun B, Shu Q, Yi W, Li X. Ogt controls neural stem/progenitor cell pool and adult neurogenesis through modulating Notch signaling. Cell Rep 2021; 34:108905. [PMID: 33789105 DOI: 10.1016/j.celrep.2021.108905] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/29/2020] [Accepted: 03/04/2021] [Indexed: 01/08/2023] Open
Abstract
Ogt catalyzed O-linked N-acetylglucosamine (O-GlcNAcylation, O-GlcNAc) plays an important function in diverse biological processes and diseases. However, the roles of Ogt in regulating neurogenesis remain largely unknown. Here, we show that Ogt deficiency or depletion in adult neural stem/progenitor cells (aNSPCs) leads to the diminishment of the aNSPC pool and aberrant neurogenesis and consequently impairs cognitive function in adult mice. RNA sequencing reveals that Ogt deficiency alters the transcription of genes relating to cell cycle, neurogenesis, and neuronal development. Mechanistic studies show that Ogt directly interacts with Notch1 and catalyzes the O-GlcNAc modification of Notch TM/ICD fragment. Decreased O-GlcNAc modification of TM/ICD increases the binding of E3 ubiquitin ligase Itch to TM/ICD and promotes its degradation. Itch knockdown rescues neurogenic defects induced by Ogt deficiency in vitro and in vivo. Our findings reveal the essential roles and mechanisms of Ogt and O-GlcNAc modification in regulating mammalian neurogenesis and cognition.
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Affiliation(s)
- Junchen Chen
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xiaoxue Dong
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xuejun Cheng
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Qiang Zhu
- MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058; The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310002, China
| | - Jinyu Zhang
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Qian Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xiaoli Huang
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Min Wang
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Liping Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China
| | - Weixiang Guo
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Binggui Sun
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310002, China; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang Province 310058, China
| | - Qiang Shu
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China.
| | - Wen Yi
- MOE Key Laboratory of Biosystems Homeostasis & Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058; The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310002, China.
| | - Xuekun Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310029, China.
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MacArthur IC, Dawlaty MM. TET Enzymes and 5-Hydroxymethylcytosine in Neural Progenitor Cell Biology and Neurodevelopment. Front Cell Dev Biol 2021; 9:645335. [PMID: 33681230 PMCID: PMC7930563 DOI: 10.3389/fcell.2021.645335] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/01/2021] [Indexed: 12/19/2022] Open
Abstract
Studies of tissue-specific epigenomes have revealed 5-hydroxymethylcytosine (5hmC) to be a highly enriched and dynamic DNA modification in the metazoan nervous system, inspiring interest in the function of this epigenetic mark in neurodevelopment and brain function. 5hmC is generated by oxidation of 5-methylcytosine (5mC), a process catalyzed by the ten–eleven translocation (TET) enzymes. 5hmC serves not only as an intermediate in DNA demethylation but also as a stable epigenetic mark. Here, we review the known functions of 5hmC and TET enzymes in neural progenitor cell biology and embryonic and postnatal neurogenesis. We also discuss how TET enzymes and 5hmC regulate neuronal activity and brain function and highlight their implications in human neurodevelopmental and neurodegenerative disorders. Finally, we present outstanding questions in the field and envision new research directions into the roles of 5hmC and TET enzymes in neurodevelopment.
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Affiliation(s)
- Ian C MacArthur
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States.,Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, United States.,Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Meelad M Dawlaty
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, United States.,Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, United States.,Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, United States
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Garcia-Outeiral V, de la Parte C, Fidalgo M, Guallar D. The Complexity of TET2 Functions in Pluripotency and Development. Front Cell Dev Biol 2021; 8:630754. [PMID: 33537318 PMCID: PMC7848104 DOI: 10.3389/fcell.2020.630754] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 12/22/2020] [Indexed: 12/14/2022] Open
Abstract
Ten-eleven translocation-2 (TET2) is a crucial driver of cell fate outcomes in a myriad of biological processes, including embryonic development and tissue homeostasis. TET2 catalyzes the demethylation of 5-methylcytosine on DNA, affecting transcriptional regulation. New exciting research has provided evidence for TET2 catalytic activity in post-transcriptional regulation through RNA hydroxymethylation. Here we review the current understanding of TET2 functions on both DNA and RNA, and the influence of these chemical modifications in normal development and pluripotency contexts, highlighting TET2 versatility in influencing genome regulation and cellular phenotypes.
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Affiliation(s)
- Vera Garcia-Outeiral
- Stem Cells and Human Diseases Group, Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Cristina de la Parte
- Epitranscriptomics and Ageing Group, Department of Biochemistry and Molecular Biology, Center for Research in Molecular Medicine and Chronic Diseases, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Miguel Fidalgo
- Stem Cells and Human Diseases Group, Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Diana Guallar
- Epitranscriptomics and Ageing Group, Department of Biochemistry and Molecular Biology, Center for Research in Molecular Medicine and Chronic Diseases, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
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Antidepressant treatment is associated with epigenetic alterations of Homer1 promoter in a mouse model of chronic depression. J Affect Disord 2021; 279:501-509. [PMID: 33128940 DOI: 10.1016/j.jad.2020.10.040] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 10/20/2020] [Accepted: 10/22/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Understanding the neurobiology of depression and the mechanism of action of therapeutic measures is currently a research priority. We have shown that the expression of the synaptic protein Homer1a correlates with depression-like behavior and its induction is a common mechanism of action of different antidepressant treatments. However, the mechanism of Homer1a regulation is still unknown. METHODS We combined the chronic despair mouse model (CDM) of chronic depression with different antidepressant treatments. Depression-like behavior was characterized by forced swim and tail suspension tests, and via automatic measurement of sucrose preference in IntelliCage. The Homer1 mRNA expression and promoter DNA methylation were analyzed in cortex and peripheral blood by qRT-PCR and pyrosequencing. RESULTS CDM mice show decreased Homer1a and Homer1b/c mRNA expression in cortex and blood samples, while chronic treatment with imipramine and fluoxetine or acute ketamine application increases their level only in the cortex. The quantitative analyses of the methylation of 7 CpG sites, located on the Homer1 promoter region containing several CRE binding sites, show a significant increase in DNA methylation in the cortex of CDM mice. In contrast, antidepressant treatments reduce the methylation level. LIMITATIONS Homer1 expression and promotor methylation were not analyzed in different blood cell types. Other CpG sites of Homer1 promoter should be investigated in future studies. Our experimental approach does not distinguish between methylation and hydroxymethylation. CONCLUSIONS We demonstrate that stress-induced depression-like behavior and antidepressant treatments are associated with epigenetic alterations of Homer1 promoter, providing new insights into the mechanism of antidepressant treatment.
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Cao Y, Kitanovski S, Hoffmann D. intePareto: an R package for integrative analyses of RNA-Seq and ChIP-Seq data. BMC Genomics 2020; 21:802. [PMID: 33372591 PMCID: PMC7771091 DOI: 10.1186/s12864-020-07205-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 10/29/2020] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND RNA-Seq, the high-throughput sequencing (HT-Seq) of mRNAs, has become an essential tool for characterizing gene expression differences between different cell types and conditions. Gene expression is regulated by several mechanisms, including epigenetically by post-translational histone modifications which can be assessed by ChIP-Seq (Chromatin Immuno-Precipitation Sequencing). As more and more biological samples are analyzed by the combination of ChIP-Seq and RNA-Seq, the integrated analysis of the corresponding data sets becomes, theoretically, a unique option to study gene regulation. However, technically such analyses are still in their infancy. RESULTS Here we introduce intePareto, a computational tool for the integrative analysis of RNA-Seq and ChIP-Seq data. With intePareto we match RNA-Seq and ChIP-Seq data at the level of genes, perform differential expression analysis between biological conditions, and prioritize genes with consistent changes in RNA-Seq and ChIP-Seq data using Pareto optimization. CONCLUSION intePareto facilitates comprehensive understanding of high dimensional transcriptomic and epigenomic data. Its superiority to a naive differential gene expression analysis with RNA-Seq and available integrative approach is demonstrated by analyzing a public dataset.
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Affiliation(s)
- Yingying Cao
- Bioinformatics and Computational Biophysics, Faculty of Biology and Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstr.2, Essen, 45141, Germany.
| | - Simo Kitanovski
- Bioinformatics and Computational Biophysics, Faculty of Biology and Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstr.2, Essen, 45141, Germany
| | - Daniel Hoffmann
- Bioinformatics and Computational Biophysics, Faculty of Biology and Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstr.2, Essen, 45141, Germany
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40
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Li L, Miao M, Chen J, Liu Z, Li W, Qiu Y, Xu S, Wang Q. Role of Ten eleven translocation-2 (Tet2) in modulating neuronal morphology and cognition in a mouse model of Alzheimer's disease. J Neurochem 2020; 157:993-1012. [PMID: 33165916 DOI: 10.1111/jnc.15234] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/31/2020] [Accepted: 11/03/2020] [Indexed: 12/19/2022]
Abstract
Abnormal expression of Ten eleven translocation-2 (Tet2) contributes to the pathogenesis of Alzheimer's disease (AD). However, to date, the role of Tet2 in modulating neuronal morphology upon amyloid-β (Aβ)-induced neurotoxicity has not been shown in a mouse model of AD. Here, we have developed a model of injured mouse hippocampal neurons induced by Aβ42 oligomers in vitro. We also investigated the role of Tet2 in injured neurons using recombinant plasmids-induced Tet2 inhibition or over-expression. We found that the reduced expression of Tet2 exacerbated neuronal damage, whereas the increased expression of Tet2 was sufficient to protect neurons against Aβ42 toxicity. Our results indicate that the brains of aged APPswe/PSEN1 double-transgenic (2 × Tg-AD) mice exhibit an increase in Aβ plaque accumulation and a decrease in Tet2 expression. As a result, we have also explored the underlying mechanisms of Tet2 in cognition and amyloid load in 2 × Tg-AD mice via adeno-associated virus-mediated Tet2 knockdown or over-expression. Recombinant adeno-associated virus was microinjected into bilateral dentate gyrus regions of the hippocampus of the mice. Knocking down Tet2 in young 2 × Tg-AD mice resulted in the same extent of cognitive dysfunction as aged 2 × Tg-AD mice. Importantly, in middle-aged 2 × Tg-AD mice, knocking down Tet2 accelerated the accumulation of Aβ plaques, whereas over-expressing Tet2 alleviated amyloid burden and memory loss. Furthermore, our hippocampal RNA-seq data, from young 2 × Tg-AD mice, were enriched with aberrantly expressed lncRNAs and miRNAs that are modulated by Tet2. Tet2-modulated lncRNAs (Malat1, Meg3, Sox2ot, Gm15477, Snhg1) and miRNAs (miR-764, miR-211, and miR-34a) may play a role in neuron formation. Overall, these results indicate that Tet2 may be a potential therapeutic target for repairing neuronal damage and cognitive impairment in AD.
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Affiliation(s)
- Liping Li
- Ningbo Key Laboratory of Behavioral Neuroscience, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China
| | - Miao Miao
- Ningbo Key Laboratory of Behavioral Neuroscience, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China
| | - Jiarui Chen
- College of Eco-Environmental Engineering, Qinghai University, Xining, Qinghai, PR China
| | - Zhitao Liu
- Faculty of Physical Education, Ningbo University, Ningbo, Zhejiang, PR China
| | - Wanyi Li
- Faculty of Physical Education, Ningbo University, Ningbo, Zhejiang, PR China
| | - Yisha Qiu
- Ningbo Key Laboratory of Behavioral Neuroscience, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China
| | - Shujun Xu
- Ningbo Key Laboratory of Behavioral Neuroscience, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China
| | - Qinwen Wang
- Ningbo Key Laboratory of Behavioral Neuroscience, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.,Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, Zhejiang, PR China
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Cheng XJ, Guan FL, Li Q, Dai G, Li HF, Li XK. AlCl 3 exposure regulates neuronal development by modulating DNA modification. World J Stem Cells 2020; 12:1354-1365. [PMID: 33312403 PMCID: PMC7705460 DOI: 10.4252/wjsc.v12.i11.1354] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 07/07/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND As the third most abundant element, aluminum is widespread in the environment. Previous studies have shown that aluminum has a neurotoxic effect and its exposure can impair neuronal development and cognitive function.
AIM To study the effects of aluminum on epigenetic modification in neural stem cells and neurons.
METHODS Neural stem cells were isolated from the forebrain of adult mice. Neurons were isolated from the hippocampi tissues of embryonic day 16-18 mice. AlCl3 at 100 and 200 μmol/L was applied to stem cells and neurons.
RESULTS Aluminum altered the differentiation of adult neural stem cells and caused apoptosis of newborn neurons while having no significant effects on the proliferation of neural stem cells. Aluminum application also significantly inhibited the dendritic development of hippocampal neurons. Mechanistically, aluminum exposure significantly affected the levels of DNA 5-hydroxy-methylcytosine, 5-methylcytosine, and N6-methyladenine in stem cells and neurons.
CONCLUSION Our findings indicate that aluminum may regulate neuronal development by modulating DNA modifications.
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Affiliation(s)
- Xue-Jun Cheng
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, Zhejiang Province, China
- The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, Zhejiang Province, China
- National Clinical Research Center for Child Health, Hangzhou 310052, Zhejiang Province, China
| | - Fu-Lai Guan
- School of Basic Medicine, Weifang Medical University, Weifang 261053, Shandong Province, China
| | - Qian Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, Zhejiang Province, China
- The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, Zhejiang Province, China
- National Clinical Research Center for Child Health, Hangzhou 310052, Zhejiang Province, China
| | - Gong Dai
- School of Basic Medicine, Weifang Medical University, Weifang 261053, Shandong Province, China
| | - Hai-Feng Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, Zhejiang Province, China
- National Clinical Research Center for Child Health, Hangzhou 310052, Zhejiang Province, China
| | - Xue-Kun Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, Zhejiang Province, China
- The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, Zhejiang Province, China
- National Clinical Research Center for Child Health, Hangzhou 310052, Zhejiang Province, China
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He C, Bozler J, Janssen KA, Wilusz JE, Garcia BA, Schorn AJ, Bonasio R. TET2 chemically modifies tRNAs and regulates tRNA fragment levels. Nat Struct Mol Biol 2020; 28:62-70. [PMID: 33230319 PMCID: PMC7855721 DOI: 10.1038/s41594-020-00526-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 09/28/2020] [Indexed: 12/16/2022]
Abstract
The ten-eleven translocation 2 (TET2) protein, which oxidizes 5-methylcytosine in DNA, can also bind RNA; however, the targets and function of TET2-RNA interactions in vivo are not fully understood. Using stringent affinity tags introduced at the Tet2 locus, we purified and sequenced TET2-crosslinked RNAs from mouse embryonic stem cells (mESCs) and found a high enrichment for tRNAs. RNA immunoprecipitation with an antibody against 5-hydroxymethylcytosine (hm5C) recovered tRNAs that overlapped with those bound to TET2 in cells. Mass spectrometry (MS) analyses revealed that TET2 is necessary and sufficient for the deposition of the hm5C modification on tRNA. Tet2 knockout in mESCs affected the levels of several small noncoding RNAs originating from TET2-bound tRNAs that were enriched by hm5C immunoprecipitation. Thus, our results suggest a new function of TET2 in promoting the conversion of 5-methylcytosine to hm5C on tRNA and regulating the processing or stability of different classes of tRNA fragments.
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Affiliation(s)
- Chongsheng He
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan Key Laboratory of Plant Functional Genomics and Developmental Regulation, Hunan University, Changsha, Hunan, P. R. China. .,Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. .,Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
| | - Julianna Bozler
- Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.,Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Kevin A Janssen
- Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.,Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.,Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Jeremy E Wilusz
- Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Benjamin A Garcia
- Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.,Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.,Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | | | - Roberto Bonasio
- Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. .,Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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Zeng Z, Xia L, Fan S, Zheng J, Qin J, Fan X, Liu Y, Tao J, Liu Y, Li K, Ling Z, Bu Y, Martin KA, Hwa J, Liu R, Tang WH. Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation. Circulation 2020; 143:354-371. [PMID: 33207953 DOI: 10.1161/circulationaha.120.049715] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Aberrant expression of circular RNA contributes to human diseases. Circular RNAs regulate gene expression by sequestering specific microRNAs. In this study, we investigated whether circMAP3K5 (circular mitogen-activated protein kinase 5) could act as a competing endogenous microRNA-22-3p (miR-22-3p) sponge and regulate neointimal hyperplasia. METHODS Circular RNA profiling from genome-wide RNA sequencing data was compared between human coronary artery smooth muscle cells (SMCs) treated with or without platelet-derived growth factor. Expression levels of circMAP3K5 were assessed in human coronary arteries from autopsies on patients with dilated cardiomyopathy or coronary heart disease. The role of circMAP3K5 in intimal hyperplasia was further investigated in mice with adeno-associated virus 9-mediated circMAP3K5 transfection. SMC-specific Tet2 (ten-eleven translocation-2) knockout mice and global miR-22-3p knockout mice were used to delineate the mechanism by which circMAP3K5 attenuated neointimal hyperplasia using the femoral arterial wire injury model. RESULTS RNA sequencing demonstrated that treatment with platelet-derived growth factor-BB significantly reduced expression of circMAP3K5 in human coronary artery SMCs. Wire-injured mouse femoral arteries and diseased arteries from patients with coronary heart disease (where platelet-derived growth factor-BB is increased) confirmed in vivo downregulation of circMAP3K5 associated with injury and disease. Lentivirus-mediated overexpression of circMAP3K5 inhibited the proliferation of human coronary artery SMCs. In vivo adeno-associated virus 9-mediated transfection of circMap3k5 (mouse circular Map3k5) specifically inhibited SMC proliferation in the wire-injured mouse arteries, resulting in reduced neointima formation. Using a luciferase reporter assay and RNA pull-down, circMAP3K5 (human circular MAP3K5) was found to sequester miR-22-3p, which, in turn, inhibited the expression of TET2. Both in vitro and in vivo results demonstrate that the loss of miR-22-3p recapitulated the antiproliferative effect of circMap3k5 on vascular SMCs. In SMC-specific Tet2 knockout mice, loss of Tet2 abolished the circMap3k5-mediated antiproliferative effect on vascular SMCs. CONCLUSIONS We identify circMAP3K5 as a master regulator of TET2-mediated vascular SMC differentiation. Targeting the circMAP3K5/miR-22-3p/TET2 axis may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia, including restenosis and atherosclerosis.
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Affiliation(s)
- Zhi Zeng
- From the Institute of Pediatrics (Z.Z., L.X., J.Q., X.F., Y.L., K.L., Z.L., Y.B., W.H.T.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China
| | - Luoxing Xia
- From the Institute of Pediatrics (Z.Z., L.X., J.Q., X.F., Y.L., K.L., Z.L., Y.B., W.H.T.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China
| | - Shunyang Fan
- Heart Center, The Third Affiliated Hospital of Zhengzhou University, China (S.F.)
| | - Junmeng Zheng
- Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangdong, China (J.Z., J.T.)
| | - Jinhong Qin
- From the Institute of Pediatrics (Z.Z., L.X., J.Q., X.F., Y.L., K.L., Z.L., Y.B., W.H.T.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China
| | - Xuejiao Fan
- From the Institute of Pediatrics (Z.Z., L.X., J.Q., X.F., Y.L., K.L., Z.L., Y.B., W.H.T.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China
| | - Yunfeng Liu
- From the Institute of Pediatrics (Z.Z., L.X., J.Q., X.F., Y.L., K.L., Z.L., Y.B., W.H.T.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China.,Clinical Laboratory (Y.L.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China
| | - Jun Tao
- Department of Cardiovascular Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangdong, China (J.Z., J.T.)
| | - Yingying Liu
- From the Institute of Pediatrics (Z.Z., L.X., J.Q., X.F., Y.L., K.L., Z.L., Y.B., W.H.T.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China.,Clinical Laboratory (Y.L.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China
| | - Kang Li
- From the Institute of Pediatrics (Z.Z., L.X., J.Q., X.F., Y.L., K.L., Z.L., Y.B., W.H.T.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China
| | - Zhenwei Ling
- From the Institute of Pediatrics (Z.Z., L.X., J.Q., X.F., Y.L., K.L., Z.L., Y.B., W.H.T.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China
| | - Yun Bu
- From the Institute of Pediatrics (Z.Z., L.X., J.Q., X.F., Y.L., K.L., Z.L., Y.B., W.H.T.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China
| | - Kathleen A Martin
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (K.A.M., J.H.)
| | - John Hwa
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT (K.A.M., J.H.)
| | - Renjing Liu
- Victor Chang Cardiac Research Institute, Sydney, Australia (R.L.)
| | - Wai Ho Tang
- From the Institute of Pediatrics (Z.Z., L.X., J.Q., X.F., Y.L., K.L., Z.L., Y.B., W.H.T.), Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China
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Bi HR, Zhou CH, Zhang YZ, Cai XD, Ji MH, Yang JJ, Chen GQ, Hu YM. Neuron-specific deletion of presenilin enhancer2 causes progressive astrogliosis and age-related neurodegeneration in the cortex independent of the Notch signaling. CNS Neurosci Ther 2020; 27:174-185. [PMID: 32961023 PMCID: PMC7816208 DOI: 10.1111/cns.13454] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 08/19/2020] [Accepted: 08/24/2020] [Indexed: 12/18/2022] Open
Abstract
Introduction Presenilin enhancer2 (Pen‐2) is an essential subunit of γ‐secretase, which is a key protease responsible for the cleavage of amyloid precursor protein (APP) and Notch. Mutations on Pen‐2 cause familial Alzheimer disease (AD). However, it remains unknown whether Pen‐2 regulates neuronal survival and neuroinflammation in the adult brain. Methods Forebrain neuron‐specific Pen‐2 conditional knockout (Pen‐2 cKO) mice were generated for this study. Pen‐2 cKO mice expressing Notch1 intracellular domain (NICD) conditionally in cortical neurons were also generated. Results Loss of Pen‐2 causes astrogliosis followed by age‐dependent cortical atrophy and neuronal loss. Loss of Pen‐2 results in microgliosis and enhanced inflammatory responses in the cortex. Expression of NICD in Pen‐2 cKO cortices ameliorates neither neurodegeneration nor neuroinflammation. Conclusions Pen‐2 is required for neuronal survival in the adult cerebral cortex. The Notch signaling may not be involved in neurodegeneration caused by loss of Pen‐2.
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Affiliation(s)
- Hui-Ru Bi
- Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Medical School, Nanjing University, Nanjing, China
| | - Cui-Hua Zhou
- Department of Anesthesiology, The Second Affiliated Changzhou People's Hospital of Nanjing Medical University, Changzhou, China
| | - Yi-Zhi Zhang
- Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Medical School, Nanjing University, Nanjing, China
| | - Xu-Dong Cai
- Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Medical School, Nanjing University, Nanjing, China
| | - Mu-Huo Ji
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jian-Jun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Gui-Quan Chen
- Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Medical School, Nanjing University, Nanjing, China
| | - Yi-Min Hu
- Department of Anesthesiology, The Second Affiliated Changzhou People's Hospital of Nanjing Medical University, Changzhou, China
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Epigenomic analysis of Parkinson's disease neurons identifies Tet2 loss as neuroprotective. Nat Neurosci 2020; 23:1203-1214. [PMID: 32807949 DOI: 10.1038/s41593-020-0690-y] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 07/07/2020] [Indexed: 01/08/2023]
Abstract
Parkinson's disease (PD) pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively examine DNA methylation at enhancers, genome-wide, in neurons of patients with PD and of control individuals. We find a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. In particular, patients with PD exhibit an epigenetic and transcriptional upregulation of TET2, a master-regulator of cytosine modification status. TET2 depletion in a neuronal cell model results in cytosine modification changes that are reciprocal to those observed in PD neurons. Moreover, Tet2 inactivation in mice fully prevents nigral dopaminergic neuronal loss induced by previous inflammation. Tet2 loss also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a new therapeutic target for PD.
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Hong JY, Davaa G, Yoo H, Hong K, Hyun JK. Ascorbic Acid Promotes Functional Restoration after Spinal Cord Injury Partly by Epigenetic Modulation. Cells 2020; 9:cells9051310. [PMID: 32466098 PMCID: PMC7290865 DOI: 10.3390/cells9051310] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/09/2020] [Accepted: 05/22/2020] [Indexed: 02/07/2023] Open
Abstract
Axonal regeneration after spinal cord injury (SCI) is difficult to achieve, and no fundamental treatment can be applied in clinical settings. DNA methylation has been suggested to play a role in regeneration capacity and neuronal growth after SCI by controlling the expression of regeneration-associated genes (RAGs). The aim of this study was to examine changes in neuronal DNA methylation status after SCI and to determine whether modulation of DNA methylation with ascorbic acid can enhance neuronal regeneration or functional restoration after SCI. Changes in epigenetic marks (5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC)); the expression of Ten-eleven translocation (Tet) family genes; and the expression of genes related to inflammation, regeneration, and degeneration in the brain motor cortex were determined following SCI. The 5hmC level within the brain was increased after SCI, especially in the acute and subacute stages, and the mRNA levels of Tet gene family members (Tet1, Tet2, and Tet3) were also increased. Administration of ascorbic acid (100 mg/kg) to SCI rats enhanced 5hmC levels; increased the expression of the Tet1, Tet2, and Tet3 genes within the brain motor cortex; promoted axonal sprouting within the lesion cavity of the spinal cord; and enhanced recovery of locomotor function until 12 weeks. In conclusion, we found that epigenetic status in the brain motor cortex is changed after SCI and that epigenetic modulation using ascorbic acid may contribute to functional recovery after SCI.
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Affiliation(s)
- Jin Young Hong
- Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea; (J.Y.H.); (G.D.)
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea
| | - Ganchimeg Davaa
- Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea; (J.Y.H.); (G.D.)
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea
| | - Hyunjin Yoo
- Department of Stem Cell & Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea;
| | - Kwonho Hong
- Department of Stem Cell & Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea;
- Correspondence: (K.H.); (J.K.H.); Tel.: +82-10-3678-7189 (K.H.); +81-10-2293-3415 (J.K.H.)
| | - Jung Keun Hyun
- Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea; (J.Y.H.); (G.D.)
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea
- Department of Rehabilitation Medicine, College of Medicine, Dankook University, Cheonan 31116, Korea
- UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan 31116, Korea
- Wiregene, Co., Ltd., Cheonan 31116, Korea
- Correspondence: (K.H.); (J.K.H.); Tel.: +82-10-3678-7189 (K.H.); +81-10-2293-3415 (J.K.H.)
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Rodríguez-Aguilera JR, Ecsedi S, Goldsmith C, Cros MP, Domínguez-López M, Guerrero-Celis N, Pérez-Cabeza de Vaca R, Chemin I, Recillas-Targa F, Chagoya de Sánchez V, Hernández-Vargas H. Genome-wide 5-hydroxymethylcytosine (5hmC) emerges at early stage of in vitro differentiation of a putative hepatocyte progenitor. Sci Rep 2020; 10:7822. [PMID: 32385352 PMCID: PMC7210258 DOI: 10.1038/s41598-020-64700-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 04/15/2020] [Indexed: 12/23/2022] Open
Abstract
A basic question linked to differential patterns of gene expression is how cells reach different fates despite using the same DNA template. Since 5-hydroxymethylcytosine (5hmC) emerged as an intermediate metabolite in active DNA demethylation, there have been increasing efforts to elucidate its function as a stable modification of the genome, including a role in establishing such tissue-specific patterns of expression. Recently we described TET1-mediated enrichment of 5hmC on the promoter region of the master regulator of hepatocyte identity, HNF4A, which precedes differentiation of liver adult progenitor cells in vitro. Here, we studied the genome-wide distribution of 5hmC at early in vitro differentiation of human hepatocyte-like cells. We found a global increase in 5hmC as well as a drop in 5-methylcytosine after one week of in vitro differentiation from bipotent progenitors, at a time when the liver transcript program is already established. 5hmC was overall higher at the bodies of overexpressed genes. Furthermore, by modifying the metabolic environment, an adenosine derivative prevents 5hmC enrichment and impairs the acquisition of hepatic identity markers. These results suggest that 5hmC could be a marker of cell identity, as well as a useful biomarker in conditions associated with cell de-differentiation such as liver malignancies.
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Affiliation(s)
- Jesús Rafael Rodríguez-Aguilera
- Department of Cellular Biology and Development, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior s/n, Ciudad Universitaria, Coyoacán, 04510, Cd. Mx., Mexico
| | - Szilvia Ecsedi
- Institute of Biology Valrose (iBV), The National Center for Scientific Research (CNRS) - National Institute of Health and Medical Research (Inserm), Université Côte d'Azur, Nice, France
| | - Chloe Goldsmith
- Department of Immunity, Virus and Inflammation. Cancer Research Centre of Lyon (CRCL), Inserm U 1052, CNRS UMR 5286, Université de Lyon, Centre Léon Bérard, 28 rue Laennec, 69373, Lyon, CEDEX 08, France
| | - Marie-Pierre Cros
- Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008, Lyon, France
| | - Mariana Domínguez-López
- Department of Cellular Biology and Development, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior s/n, Ciudad Universitaria, Coyoacán, 04510, Cd. Mx., Mexico
| | - Nuria Guerrero-Celis
- Department of Cellular Biology and Development, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior s/n, Ciudad Universitaria, Coyoacán, 04510, Cd. Mx., Mexico
| | - Rebeca Pérez-Cabeza de Vaca
- Department of Cellular Biology and Development, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior s/n, Ciudad Universitaria, Coyoacán, 04510, Cd. Mx., Mexico
- Division of Biomedical Research, Centro Médico Nacional "20 de noviembre", ISSSTE, San Lorenzo 502, Benito Juárez, 03100, Cd. Mx., Mexico
| | - Isabelle Chemin
- INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon Université Claude Bernard, Lyon, France
| | - Félix Recillas-Targa
- Department of Molecular Genetics, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior s/n, Ciudad Universitaria, Coyoacán, 04510, Cd. Mx., Mexico
| | - Victoria Chagoya de Sánchez
- Department of Cellular Biology and Development, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior s/n, Ciudad Universitaria, Coyoacán, 04510, Cd. Mx., Mexico.
| | - Héctor Hernández-Vargas
- Department of Immunity, Virus and Inflammation. Cancer Research Centre of Lyon (CRCL), Inserm U 1052, CNRS UMR 5286, Université de Lyon, Centre Léon Bérard, 28 rue Laennec, 69373, Lyon, CEDEX 08, France.
- Department of Translational Research and Innovation. Centre Léon Bérard, 28 rue Laennec, 69373, Lyon, CEDEX 08, France.
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Cochran JN, Geier EG, Bonham LW, Newberry JS, Amaral MD, Thompson ML, Lasseigne BN, Karydas AM, Roberson ED, Cooper GM, Rabinovici GD, Miller BL, Myers RM, Yokoyama JS. Non-coding and Loss-of-Function Coding Variants in TET2 are Associated with Multiple Neurodegenerative Diseases. Am J Hum Genet 2020; 106:632-645. [PMID: 32330418 PMCID: PMC7212268 DOI: 10.1016/j.ajhg.2020.03.010] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 03/20/2020] [Indexed: 12/13/2022] Open
Abstract
We conducted genome sequencing to search for rare variation contributing to early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 435 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than one in 10,000 or private), computational prediction of deleteriousness (CADD) (10 or 15 thresholds), and molecular function (protein loss-of-function [LoF] only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions). Replication analysis was conducted on 16,434 independent cases and 15,587 independent controls. Rare variants in TET2 were enriched in the discovery combined EOAD and FTD cohort (p = 4.6 × 10-8, genome-wide corrected p = 0.0026). Most of these variants were canonical LoF or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of Alzheimer's disease (AD) and FTD (replication only p = 0.0029). The combined analysis odds ratio was 2.3 (95% confidence interval [CI] 1.6-3.4) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 3.7 (95% CI 1.7-9.4). For LoF variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.1 (95% CI 1.9-5.2). TET2 catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in TET2 may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.
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Affiliation(s)
- J Nicholas Cochran
- HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, United States
| | - Ethan G Geier
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, United States
| | - Luke W Bonham
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, United States
| | - J Scott Newberry
- HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, United States
| | - Michelle D Amaral
- HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, United States
| | - Michelle L Thompson
- HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, United States
| | - Brittany N Lasseigne
- HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, United States; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - Anna M Karydas
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, United States
| | - Erik D Roberson
- Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| | - Gregory M Cooper
- HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, United States
| | - Gil D Rabinovici
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, United States; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94158, United States
| | - Bruce L Miller
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, United States
| | - Richard M Myers
- HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, United States
| | - Jennifer S Yokoyama
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, United States; Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94158, United States.
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Plastrum Testudinis Extracts Promote NSC Differentiation into Dopaminergic Neuron by Regulating the Interaction of TET1 and FoxA2. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:9104135. [PMID: 32382312 PMCID: PMC7189310 DOI: 10.1155/2020/9104135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 02/24/2020] [Accepted: 03/06/2020] [Indexed: 12/02/2022]
Abstract
In recent years, stem cells have gained much attention for the treatment of neurodegenerative diseases. However, inducing neural stem cell directionally differentiation is a difficult problem in the treatment of Parkinson's disease (PD) by stem cell therapy. Plastrum Testudinis (PT) can enhance the number of TH-positive neurons in the PD rat brain substantia nigra, but the underlying mechanism has not been clarified. Here, we aimed at further investigating the mechanism by which PT can promote NSC differentiation into dopaminergic neurons. A rat model of PD was used for detecting the effect of PT on the rat brain substantia nigra in vivo. The results showed the expressions of tyrosine hydroxylase (TH) and TET1 enzyme were increased after treatment with PT. Consequently, Plastrum Testudinis extracts (PTEs) were used for inducing NSC differentiation into dopaminergic neurons ex vivo. During differentiation of NSCs induced by PTE, TH expression was increased, with a concomitant increase in both TET1 and FoxA2. Next, we performed coimmunoprecipitation analysis to examine the interaction between TET1 protein and FoxA2 protein. Our results show that PTE can increase the binding rate of TET1 and FoxA2. Thus, our findings show that PTE can increase the efficiency of NSCs to directionally differentiate into dopaminergic neurons and provide experimental evidence for PT in the treatment of Parkinson's disease.
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50
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Takaki N, Uchiwa T, Furuse M, Yasuo S. Effect of postnatal photoperiod on DNA methylation dynamics in the mouse brain. Brain Res 2020; 1733:146725. [DOI: 10.1016/j.brainres.2020.146725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 10/26/2019] [Accepted: 02/10/2020] [Indexed: 02/06/2023]
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