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Ali F, Almuhaimeed A, Alghamdi W, Aldossary H, Asiry O, Masmoudi A. Leveraging deep learning for epigenetic protein prediction: a novel approach for early lung cancer diagnosis and drug discovery. Health Inf Sci Syst 2025; 13:28. [PMID: 40083337 PMCID: PMC11896910 DOI: 10.1007/s13755-025-00347-5] [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: 07/26/2024] [Accepted: 01/21/2025] [Indexed: 03/16/2025] Open
Abstract
Epigenetic protein (EP) plays a crucial role in influencing disease development, controlling gene expression, and shaping cell identity. They hold potential as targets for future therapies, and studying their mechanisms can lead to improved diagnosis and treatment strategies for various diseases. Anticipating EP is imperative, yet conventional experimental approaches for prediction prove time-intensive and expensive. This work constructed CNN-BiLSTM, computational method for identification of EP prediction. Utilizing primary sequences, two datasets were constructed, and an amphiphilic pseudo amino acid, group dipeptide composition and group amino acid composition were devised to extract numerical features. Model training incorporated a suite of deep learning architectures, including BiLSTM, GRU, and CNN. Notably, an ensemble model combining CNN and BiLSTM, trained using AmpPseAAC features, demonstrated superior performance across both training and testing datasets compared to other predictors. This research contributes to the ongoing efforts to revolutionize therapeutic approaches by facilitating the identification of novel drug targets and improving disease treatment outcomes.
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Affiliation(s)
- Farman Ali
- Department of Computer Science, Bahria University Islamabad Campus, Islamabad, Pakistan
| | - Abdullah Almuhaimeed
- King Abdulaziz City for Science and Technology, Digital Health Institute, 11442 Riyadh, Saudi Arabia
| | - Wajdi Alghamdi
- Department of Information Technology, Faculty of Computing and Information Technology, King Abdulaziz University, 21589 Jeddah, Saudi Arabia
| | - Haya Aldossary
- Computer Science Department, College of Science and Humanities, Imam Abdulrahman Bin Faisal University, 31961 Jubail, Saudi Arabia
| | - Othman Asiry
- Department of Information Technology, College of Computing and Information Technology at Khulais, University of Jeddah, Jeddah, Saudi Arabia
| | - Atef Masmoudi
- Department of Computer Science, College of Computer Science, King Khalid University, 61421 Abha, Saudi Arabia
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2
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Olawade DB, Rashad I, Egbon E, Teke J, Ovsepian SV, Boussios S. Reversing Epigenetic Dysregulation in Neurodegenerative Diseases: Mechanistic and Therapeutic Considerations. Int J Mol Sci 2025; 26:4929. [PMID: 40430067 PMCID: PMC12112518 DOI: 10.3390/ijms26104929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2025] [Revised: 05/05/2025] [Accepted: 05/19/2025] [Indexed: 05/29/2025] Open
Abstract
Epigenetic dysregulation has emerged as an important player in the pathobiology of neurodegenerative diseases (NDDs), such as Alzheimer's, Parkinson's, and Huntington's diseases. Aberrant DNA methylation, histone modifications, and dysregulated non-coding RNAs have been shown to contribute to neuronal dysfunction and degeneration. These alterations are often exacerbated by environmental toxins, which induce oxidative stress, inflammation, and genomic instability. Reversing epigenetic aberrations may offer an avenue for restoring brain mechanisms and mitigating neurodegeneration. Herein, we revisit the evidence suggesting the ameliorative effects of epigenetic modulators in toxin-induced models of NDDs. The restoration of normal gene expressions, the improvement of neuronal function, and the reduction in pathological markers by histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors have been demonstrated in preclinical models of NDDs. Encouragingly, in clinical trials of Alzheimer's disease (AD), HDAC inhibitors have caused improvements in cognition and memory. Combining these beneficial effects of epigenetic modulators with neuroprotective agents and the clearance of misfolded amyloid proteins may offer synergistic benefits. Reinforced by the emerging methods for more effective and brain-specific delivery, reversibility, and safety considerations, epigenetic modulators are anticipated to minimize systemic toxicity and yield more favorable outcomes in NDDs. In summary, although still in their infancy, epigenetic modulators offer an integrated strategy to address the multifactorial nature of NDDs, altering their therapeutic landscape.
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Affiliation(s)
- David B. Olawade
- Department of Allied and Public Health, School of Health, Sport and Bioscience, University of East London, London E16 2RD, UK;
- Department of Research and Innovation, Medway NHS Foundation Trust, Gillingham ME7 5NY, UK;
- Department of Public Health, York St John University, London E14 2BA, UK
- School of Health and Care Management, Arden University, Arden House, Middlemarch Park, Coventry CV3 4FJ, UK
| | - Intishar Rashad
- Department of Acute Medicine, Medway NHS Foundation Trust, Gillingham ME7 5NY, UK
| | - Eghosasere Egbon
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Life Science Engineering, FH Technikum, 1200 Vienna, Austria;
| | - Jennifer Teke
- Department of Research and Innovation, Medway NHS Foundation Trust, Gillingham ME7 5NY, UK;
- Faculty of Medicine, Health and Social Care, Canterbury Christ Church University, Canterbury CT1 1QU, UK
| | - Saak Victor Ovsepian
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime ME4 4TB, UK;
- Faculty of Medicine, Tbilisi State University, Tbilisi 0177, Georgia
| | - Stergios Boussios
- Department of Research and Innovation, Medway NHS Foundation Trust, Gillingham ME7 5NY, UK;
- Faculty of Medicine, Health and Social Care, Canterbury Christ Church University, Canterbury CT1 1QU, UK
- Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King’s College London, London WC2R 2LS, UK
- Kent Medway Medical School, University of Kent, Canterbury CT2 7LX, UK
- AELIA Organization, 9th Km Thessaloniki—Thermi, 57001 Thessaloniki, Greece
- Department of Medical Oncology, Medway NHS Foundation Trust, Gillingham ME7 5NY, UK
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Ratinho L, Meyer N, Greive S, Cressiot B, Pelta J. Nanopore sensing of protein and peptide conformation for point-of-care applications. Nat Commun 2025; 16:3211. [PMID: 40180898 PMCID: PMC11968944 DOI: 10.1038/s41467-025-58509-8] [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: 09/07/2024] [Accepted: 03/25/2025] [Indexed: 04/05/2025] Open
Abstract
The global population's aging and growth will likely result in an increase in chronic aging-related diseases. Early diagnosis could improve the medical care and quality of life. Many diseases are linked to misfolding or conformational changes in biomarker peptides and proteins, which affect their function and binding properties. Current clinical methods struggle to detect and quantify these changes. Therefore, there is a need for sensitive conformational sensors that can detect low-concentration analytes in biofluids. Nanopore electrical detection has shown potential in sensing subtle protein and peptide conformation changes. This technique can detect single molecules label-free while distinguishing shape or physicochemical property changes. Its proven sensitivity makes nanopore sensing technology promising for ultra-sensitive, personalized point-of-care devices. We focus on the capability of nanopore sensing for detecting and quantifying conformational modifications and enantiomers in biomarker proteins and peptides and discuss this technology as a solution to future societal health challenges.
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Affiliation(s)
- Laura Ratinho
- Université Paris-Saclay, Univ Evry, CY Cergy Paris Université, CNRS, LAMBE, Cergy, France
| | - Nathan Meyer
- Université Paris-Saclay, Univ Evry, CY Cergy Paris Université, CNRS, LAMBE, Cergy, France
| | | | - Benjamin Cressiot
- Université Paris-Saclay, Univ Evry, CY Cergy Paris Université, CNRS, LAMBE, Cergy, France.
| | - Juan Pelta
- Université Paris-Saclay, Univ Evry, CY Cergy Paris Université, CNRS, LAMBE, Evry-Courcouronnes, France.
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Sethi P, Mehan S, Khan Z, Maurya PK, Kumar N, Kumar A, Tiwari A, Sharma T, Das Gupta G, Narula AS, Kalfin R. The SIRT-1/Nrf2/HO-1 axis: Guardians of neuronal health in neurological disorders. Behav Brain Res 2025; 476:115280. [PMID: 39368713 DOI: 10.1016/j.bbr.2024.115280] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/10/2024] [Accepted: 09/30/2024] [Indexed: 10/07/2024]
Abstract
SIRT1 (Sirtuin 1) is a NAD+-dependent deacetylase that functions through nucleoplasmic transfer and is present in nearly all mammalian tissues. SIRT1 is believed to deacetylate its protein substrates, resulting in neuroprotective actions, including reduced oxidative stress and inflammation, increased autophagy, increased nerve growth factors, and preserved neuronal integrity in aging or neurological disease. Nrf2 is a transcription factor that regulates the genes responsible for oxidative stress response and substance detoxification. The activation of Nrf2 guards cells against oxidative damage, inflammation, and carcinogenic stimuli. Several neurological abnormalities and inflammatory disorders have been associated with variations in Nrf2 activation caused by either pharmacological or genetic factors. Recent evidence indicates that Nrf2 is at the center of a complex cellular regulatory network, establishing it as a transcription factor with genuine pleiotropy. HO-1 is most likely a component of a defense mechanism in cells under stress, as it provides negative feedback for cell activation and mediator synthesis. This mediator is upregulated by Nrf2, nitric oxide (NO), and other factors in various inflammatory states. HO-1 or its metabolites, such as CO, may mitigate inflammation by modulating signal transduction pathways. Neurological diseases may be effectively treated by modulating the activity of HO-1. Multiple studies have demonstrated that SIRT1 and Nrf2 share an important connection. SIRT1 enhances Nrf2, activates HO-1, protects against oxidative injury, and decreases neuronal death. This has been associated with numerous neurodegenerative and neuropsychiatric disorders. Therefore, activating the SIRT1/Nrf2/HO-1 pathway may help treat various neurological disorders. This review focuses on the current understanding of the SIRT1 and Nrf2/HO-1 neuroprotective processes and the potential therapeutic applications of their target activators in neurodegenerative and neuropsychiatric disorders.
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Affiliation(s)
- Pranshul Sethi
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Sidharth Mehan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India.
| | - Zuber Khan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Pankaj Kumar Maurya
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh 201204, India
| | - Aakash Kumar
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Aarti Tiwari
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Tarun Sharma
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Ghanshyam Das Gupta
- Department of Pharmaceutics, ISF College of Pharmacy (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Acharan S Narula
- Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC 27516, USA
| | - Reni Kalfin
- Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. G. Bonchev St., Block 23, Sofia 1113, Bulgaria; Department of Healthcare, South-West University "NeofitRilski", Ivan Mihailov St. 66, Blagoevgrad 2700, Bulgaria
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van Zundert B, Montecino M. Epigenetics in Neurodegenerative Diseases. Subcell Biochem 2025; 108:73-109. [PMID: 39820861 DOI: 10.1007/978-3-031-75980-2_3] [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] [Indexed: 01/19/2025]
Abstract
Healthy brain functioning requires a continuous fine-tuning of gene expression, involving changes in the epigenetic landscape and 3D chromatin organization. Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are three multifactorial neurodegenerative diseases (NDDs) that are partially explained by genetics (gene mutations and genetic risk factors) and influenced by non-genetic factors (i.e., aging, lifestyle, and environmental conditions). Examining comprehensive studies of global and locus-specific (epi)genomic and transcriptomic alterations in human and mouse brain samples at the cell-type resolution has uncovered important phenomena associated with AD. First, DNA methylation and histone marks at promoters contribute to transcriptional dysregulation of genes that are directly implicated in AD pathogenesis (i.e., APP), neuroplasticity and cognition (i.e., PSD95), and microglial activation (i.e., TREM2). Second, the presence of AD genetic risk variants in cell-type-specific distal enhancers (i.e., BIN1 in microglia) alters transcription, presumably by disrupting associated enhancer-promoter interactions and chromatin looping. Third, epigenomic erosion is associated with widespread transcriptional disruption and cell identity loss. And fourth, aging, high cholesterol, air pollution, and pesticides have emerged as potential drivers of AD by inducing locus-specific and global epigenetic modifications that impact key AD-related pathways. Epigenetic studies in ALS/FTD also provide evidence that genetic and non-genetic factors alter gene expression profiles in neurons and astrocytes through aberrant epigenetic mechanisms. We additionally overview the recent development of potential new therapeutic strategies involving (epi)genetic editing and the use of small chromatin-modifying molecules (epidrugs).
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Affiliation(s)
- Brigitte van Zundert
- Faculty of Medicine and Faculty of Life Sciences, Institute of Biomedical Sciences (ICB), Universidad Andres Bello, Santiago, Chile.
- Millennium Nucleus of Neuroepigenetics and Plasticity (EpiNeuro), Santiago, Chile.
- Department of Neurology, University of Massachusetts Chan Medical School (UMMS), Worcester, MA, USA.
| | - Martin Montecino
- Faculty of Medicine and Faculty of Life Sciences, Institute of Biomedical Sciences (ICB), Universidad Andres Bello, Santiago, Chile.
- Millennium Nucleus of Neuroepigenetics and Plasticity (EpiNeuro), Santiago, Chile.
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Abstract
In animals, memory formation and recall are essential for their survival and for adaptations to a complex and often dynamically changing environment. During memory formation, experiences prompt the activation of a selected and sparse population of cells (engram cells) that undergo persistent physical and/or chemical changes allowing long-term memory formation, which can last for decades. Over the past few decades, important progress has been made on elucidating signaling mechanisms by which synaptic transmission leads to the induction of activity-dependent gene regulation programs during the different phases of learning (acquisition, consolidation, and recall). But what are the molecular mechanisms that govern the expression of immediate-early genes (IEGs; c-fos, Npas4) and plasticity-related genes (PRGs; Dlg4/PSD95 and Grin2b/NR2B) in memory ensemble? Studies in relatively simple in vitro and in vivo neuronal model systems have demonstrated that synaptic activity during development, or when induced by chemical stimuli (i.e., cLTP, KCl, picrotoxin), activates the NMDAR-Ca2+-CREB signaling pathway that upregulates gene expression through changes in the epigenetic landscape (i.e., histone marks and DNA methylation) and/or 3D chromatin organization. The data support a model in which epigenetic modifications in promoters and enhancers facilitate the priming and activation of these regulatory regions, hence leading to the formation of enhancer-promoter interactions (EPIs) through chromatin looping. The exploration of whether similar molecular mechanisms drive gene expression in learning and memory has presented notable challenges due to the distinct phases of learning and the activation of only sparse population of cells (the engram). Consequently, such studies demand precise temporal and spatial control. By combining activity-dependent engram tagging strategies (i.e., TRAP mice) with multi-omics analyses (i.e., RNA-seq, ChiP-seq, ATAC-seq, and Hi-C), it has been recently possible to associate changes in the epigenomic landscape and/or 3D genome architecture with transcriptional waves in engram cells of mice subjected to contextual fear conditioning (CFC), a relevant one-shot Pavlovian learning task. These studies support the role of specific epigenetic mechanisms and of the 3D chromatin organization during the control of gene transcription waves in engram cells. Advancements in our comprehension of the molecular mechanisms driving memory ensemble will undoubtedly play a crucial role in the development of better-targeted strategies to tackle cognitive diseases, including Alzheimer's disease and frontotemporal dementia, among other information-processing disorders.
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Affiliation(s)
- Brigitte van Zundert
- Faculty of Medicine and Faculty of Life Sciences, Institute of Biomedical Sciences (ICB), Universidad Andres Bello, Santiago, Chile.
- Millennium Nucleus of Neuroepigenetics and Plasticity (EpiNeuro), Santiago, Chile.
- Department of Neurology, University of Massachusetts Chan Medical School (UMMS), Worcester, MA, USA.
| | - Martin Montecino
- Faculty of Medicine and Faculty of Life Sciences, Institute of Biomedical Sciences (ICB), Universidad Andres Bello, Santiago, Chile.
- Millennium Nucleus of Neuroepigenetics and Plasticity (EpiNeuro), Santiago, Chile.
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7
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Li T, Chen X, Tong W. Bridging organ transcriptomics for advancing multiple organ toxicity assessment with a generative AI approach. NPJ Digit Med 2024; 7:310. [PMID: 39501092 PMCID: PMC11538515 DOI: 10.1038/s41746-024-01317-z] [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: 04/30/2024] [Accepted: 10/25/2024] [Indexed: 11/08/2024] Open
Abstract
Translational research in toxicology has significantly benefited from transcriptomic profiling, particularly in drug safety. However, its application has predominantly focused on limited organs, notably the liver, due to resource constraints. This paper presents TransTox, an innovative AI model using a generative adversarial network (GAN) method to facilitate the bidirectional translation of transcriptomic profiles between the liver and kidney under drug treatment. TransTox demonstrates robust performance, validated across independent datasets and laboratories. First, the concordance between real experimental data and synthetic data generated by TransTox was demonstrated in characterizing toxicity mechanisms compared to real experimental settings. Second, TransTox proved valuable in gene expression predictive models, where synthetic data could be used to develop gene expression predictive models or serve as "digital twins" for diagnostic applications. The TransTox approach holds the potential for multi-organ toxicity assessment with AI and advancing the field of precision toxicology.
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Affiliation(s)
- Ting Li
- FDA National Center for Toxicological Research, Jefferson, AR, USA
| | - Xi Chen
- FDA National Center for Toxicological Research, Jefferson, AR, USA
| | - Weida Tong
- FDA National Center for Toxicological Research, Jefferson, AR, USA.
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Goh JY, Rueda P, Taylor J, Rathbone A, Scott D, Langmead CJ, Fone KC, Stewart GD, King MV. Transcriptomic analysis of rat prefrontal cortex following chronic stress induced by social isolation - Relevance to psychiatric and neurodevelopmental illness, and implications for treatment. Neurobiol Stress 2024; 33:100679. [PMID: 39502833 PMCID: PMC11536066 DOI: 10.1016/j.ynstr.2024.100679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/27/2024] [Accepted: 10/10/2024] [Indexed: 11/08/2024] Open
Abstract
Social isolation is an established risk factor for psychiatric illness, and became increasingly topical with the spread of SARS-CoV-2. We used RNA sequencing (RNA-Seq) to enable unbiased assessment of transcriptomic changes within the prefrontal cortex (PFC) of isolation-reared rats. To provide insight into the relevance of this manipulation for studying human illness, we compared differentially expressed genes (DEGs) and enriched biological functions against datasets involving post-mortem frontal cortical tissue from patients with psychiatric and neurodevelopmental illnesses. Sixteen male Sprague-Dawley rats were reared in groups of four or individually from weaning on postnatal day (PND) 22-24 until PFC tissue collection for RNA-Seq (PND64-66). We identified a total of 183 DEGs in isolates, of which 128 mirrored those in PFC tissue from patients with stress-related mental illnesses and/or neurodevelopmental conditions featuring social deficits. Seventy-one encode proteins classed as druggable by the gene-drug interaction database. Interestingly there are antagonists or inhibitors for the products of three of these up-regulated DEGs (Hrh3, Snca and Sod1) and agonists or activators for products of six of these down-regulated DEGs (Chrm4, Klf2, Lrrk2, Nr4a1, Nr4a3 and Prkca). Some have already undergone pre-clinical and clinical evaluation, and studies with the remainder may be warranted. Changes to Hrh3, Sod1, Chrm4, Lrrk2, Nr4a1 and Prkca were replicated in an independent cohort of sixteen male Sprague-Dawley rats via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our findings support the continued use of post-weaning isolation rearing to investigate the neurobiology of stress-related disorders and evaluate therapeutic targets.
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Affiliation(s)
- Jen-Yin Goh
- Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Patricia Rueda
- Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Joy Taylor
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Alex Rathbone
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Daniel Scott
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Christopher J. Langmead
- Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Kevin C.F. Fone
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Gregory D. Stewart
- Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Madeleine V. King
- School of Life Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
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Komoto Y, Ohshiro T, Notsu Y, Taniguchi M. Single-molecule detection of modified amino acid regulating transcriptional activity. RSC Adv 2024; 14:31740-31744. [PMID: 39376514 PMCID: PMC11457157 DOI: 10.1039/d4ra05488a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 09/20/2024] [Indexed: 10/09/2024] Open
Abstract
Acetylation of lysine, a component of histones, regulates transcriptional activity. Simple detection methods for acetyl lysine are essential for early diagnosis of diseases and understanding of the physiological effects. We have detected and recognized acetyl lysine at the single-molecule level by combining MCBJ measurement and machine learning.
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Affiliation(s)
- Yuki Komoto
- SANKEN, Osaka University 8-1, Mihogaoka Ibaraki Osaka 567-0047 Japan
- Artificial Intelligence Research Center, Osaka University 8-1 Mihogaoka, Ibaraki Osaka 567-0047 Japan
| | - Takahito Ohshiro
- SANKEN, Osaka University 8-1, Mihogaoka Ibaraki Osaka 567-0047 Japan
- Artificial Intelligence Research Center, Osaka University 8-1 Mihogaoka, Ibaraki Osaka 567-0047 Japan
| | - Yuno Notsu
- Kakogawa Higashi High School 232-2 Kakogawachoawazu Kakogawa Hyogo 675-0039 Japan
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Santoni G, Astori S, Leleu M, Glauser L, Zamora SA, Schioppa M, Tarulli I, Sandi C, Gräff J. Chromatin plasticity predetermines neuronal eligibility for memory trace formation. Science 2024; 385:eadg9982. [PMID: 39052786 DOI: 10.1126/science.adg9982] [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: 02/03/2023] [Revised: 03/01/2024] [Accepted: 05/24/2024] [Indexed: 07/27/2024]
Abstract
Memories are encoded by sparse populations of neurons but how such sparsity arises remains largely unknown. We found that a neuron's eligibility to be recruited into the memory trace depends on its epigenetic state prior to encoding. Principal neurons in the mouse lateral amygdala display intrinsic chromatin plasticity, which when experimentally elevated favors neuronal allocation into the encoding ensemble. Such chromatin plasticity occurred at genomic regions underlying synaptic plasticity and was accompanied by increased neuronal excitability in single neurons in real time. Lastly, optogenetic silencing of the epigenetically altered neurons prevented memory expression, revealing a cell-autonomous relationship between chromatin plasticity and memory trace formation. These results identify the epigenetic state of a neuron as a key factor enabling information encoding.
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Affiliation(s)
- Giulia Santoni
- Laboratory of Neuroepigenetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Simone Astori
- Laboratory of Behavioural Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Marion Leleu
- Bioinformatics Competence Center, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Liliane Glauser
- Laboratory of Neuroepigenetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Simon A Zamora
- Laboratory of Neuroepigenetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Myriam Schioppa
- Laboratory of Neuroepigenetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
- The institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK
| | - Isabella Tarulli
- Laboratory of Neuroepigenetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Carmen Sandi
- Laboratory of Behavioural Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Johannes Gräff
- Laboratory of Neuroepigenetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
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11
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Abdalla MMI. Insulin resistance as the molecular link between diabetes and Alzheimer's disease. World J Diabetes 2024; 15:1430-1447. [PMID: 39099819 PMCID: PMC11292327 DOI: 10.4239/wjd.v15.i7.1430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/08/2024] [Accepted: 05/06/2024] [Indexed: 07/08/2024] Open
Abstract
Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies have indicated a possible link between DM and an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays a vital role in protecting brain functions. Insulin resistance (IR), especially prevalent in type 2 diabetes, is believed to play a significant role in AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various brain functions, making individuals more susceptible to AD's defining features, such as the buildup of beta-amyloid plaques and tau protein tangles. Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD. This review aims to explore the rela-tionship between DM and AD, with a focus on the role of IR. It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR. Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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Huang M, Tao X, Bao J, Wang J, Gong X, Luo L, Pan S, Yang R, Gui Y, Zhou H, Xia Y, Yang Y, Sun B, Liu W, Shu X. GADD45B in the ventral hippocampal CA1 modulates aversive memory acquisition and spatial cognition. Life Sci 2024; 346:122618. [PMID: 38614306 DOI: 10.1016/j.lfs.2024.122618] [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: 02/03/2024] [Revised: 04/01/2024] [Accepted: 04/05/2024] [Indexed: 04/15/2024]
Abstract
AIMS This study was designed to investigate the role of growth arrest and DNA damage-inducible β (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. MAIN METHODS Adeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. KEY FINDINGS Knockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. SIGNIFICANCE These results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition.
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Affiliation(s)
- Mengbing Huang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Xiaoqing Tao
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Jian Bao
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Ji Wang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Xiaokang Gong
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Laijie Luo
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Sijie Pan
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Rong Yang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Yuran Gui
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - HongYan Zhou
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Yiyuan Xia
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Youhua Yang
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Binlian Sun
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
| | - Wei Liu
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China.
| | - Xiji Shu
- Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China.
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Yao Q, Long C, Yi P, Zhang G, Wan W, Rao X, Ying J, Liang W, Hua F. C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease. CNS Neurosci Ther 2024; 30:e14721. [PMID: 38644578 PMCID: PMC11033503 DOI: 10.1111/cns.14721] [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: 11/15/2023] [Revised: 03/20/2024] [Accepted: 03/27/2024] [Indexed: 04/23/2024] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment. AIMS Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD. METHODS A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded. RESULTS Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO). DISCUSSION The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS). CONCLUSION The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.
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Affiliation(s)
- Qing Yao
- Department of AnesthesiologyThe Second Affiliated Hospital of Nanchang UniversityNanchang CityJiangxi ProvinceChina
- Key Laboratory of Anesthesiology of Jiangxi ProvinceNanchang CityJiangxi ProvinceChina
| | - Chubing Long
- Department of AnesthesiologyThe Second Affiliated Hospital of Nanchang UniversityNanchang CityJiangxi ProvinceChina
- Key Laboratory of Anesthesiology of Jiangxi ProvinceNanchang CityJiangxi ProvinceChina
| | - Pengcheng Yi
- Department of AnesthesiologyThe Second Affiliated Hospital of Nanchang UniversityNanchang CityJiangxi ProvinceChina
- Key Laboratory of Anesthesiology of Jiangxi ProvinceNanchang CityJiangxi ProvinceChina
| | - Guangyong Zhang
- Department of AnesthesiologyThe Second Affiliated Hospital of Nanchang UniversityNanchang CityJiangxi ProvinceChina
- Key Laboratory of Anesthesiology of Jiangxi ProvinceNanchang CityJiangxi ProvinceChina
| | - Wei Wan
- Department of AnesthesiologyThe Second Affiliated Hospital of Nanchang UniversityNanchang CityJiangxi ProvinceChina
- Key Laboratory of Anesthesiology of Jiangxi ProvinceNanchang CityJiangxi ProvinceChina
| | - Xiuqin Rao
- Department of AnesthesiologyThe Second Affiliated Hospital of Nanchang UniversityNanchang CityJiangxi ProvinceChina
- Key Laboratory of Anesthesiology of Jiangxi ProvinceNanchang CityJiangxi ProvinceChina
| | - Jun Ying
- Department of AnesthesiologyThe Second Affiliated Hospital of Nanchang UniversityNanchang CityJiangxi ProvinceChina
- Key Laboratory of Anesthesiology of Jiangxi ProvinceNanchang CityJiangxi ProvinceChina
| | - Weidong Liang
- Department of AnesthesiologyThe First Affiliated Hospital of Gannan Medical UniversityGanzhouJiangxi ProvinceChina
| | - Fuzhou Hua
- Department of AnesthesiologyThe Second Affiliated Hospital of Nanchang UniversityNanchang CityJiangxi ProvinceChina
- Key Laboratory of Anesthesiology of Jiangxi ProvinceNanchang CityJiangxi ProvinceChina
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14
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Coda DM, Gräff J. From cellular to fear memory: An epigenetic toolbox to remember. Curr Opin Neurobiol 2024; 84:102829. [PMID: 38128422 DOI: 10.1016/j.conb.2023.102829] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 12/23/2023]
Abstract
Throughout development, the neuronal epigenome is highly sensitive to external stimuli, yet capable of safeguarding cellular memory for a lifetime. In the adult brain, memories of fearful experiences are rapidly instantiated, yet can last for decades, but the mechanisms underlying such longevity remain unknown. Here, we showcase how fear memory formation and storage - traditionally thought to exclusively affect synapse-based events - elicit profound and enduring changes to the chromatin, proposing epigenetic regulation as a plausible molecular template for mnemonic processes. By comparing these to mechanisms occurring in development and differentiation, we notice that an epigenetic machinery similar to that preserving cellular memories might be employed by brain cells so as to form, store, and retrieve behavioral memories.
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Affiliation(s)
- Davide Martino Coda
- Laboratory of Neuroepigenetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Federale Lausanne (EPFL), 1015, Lausanne, Switzerland.
| | - Johannes Gräff
- Laboratory of Neuroepigenetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Federale Lausanne (EPFL), 1015, Lausanne, Switzerland.
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15
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Fuentes-Ramos M, Barco Á. Unveiling Transcriptional and Epigenetic Mechanisms Within Engram Cells: Insights into Memory Formation and Stability. ADVANCES IN NEUROBIOLOGY 2024; 38:111-129. [PMID: 39008013 DOI: 10.1007/978-3-031-62983-9_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Memory traces for behavioral experiences, such as fear conditioning or taste aversion, are believed to be stored through biophysical and molecular changes in distributed neuronal ensembles across various brain regions. These ensembles are known as engrams, and the cells that constitute them are referred to as engram cells. Recent advancements in techniques for labeling and manipulating neural activity have facilitated the study of engram cells throughout different memory phases, including acquisition, allocation, long-term storage, retrieval, and erasure. In this chapter, we will explore the application of next-generation sequencing methods to engram research, shedding new light on the contribution of transcriptional and epigenetic mechanisms to engram formation and stability.
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Affiliation(s)
- Miguel Fuentes-Ramos
- Instituto de Neurociencias, Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas, Alicante, Spain
| | - Ángel Barco
- Instituto de Neurociencias, Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas, Alicante, Spain.
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16
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Zhang W, Oh JH, Zhang W, Rathi S, Larson JD, Wechsler-Reya RJ, Sirianni RW, Elmquist WF. Central Nervous System Distribution of Panobinostat in Preclinical Models to Guide Dosing for Pediatric Brain Tumors. J Pharmacol Exp Ther 2023; 387:315-327. [PMID: 37827699 PMCID: PMC10658912 DOI: 10.1124/jpet.123.001826] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 09/24/2023] [Accepted: 09/28/2023] [Indexed: 10/14/2023] Open
Abstract
Achieving adequate exposure of the free therapeutic agent at the target is a critical determinant of efficacious chemotherapy. With this in mind, a major challenge in developing therapies for central nervous system (CNS) tumors is to overcome barriers to delivery, including the blood-brain barrier (BBB). Panobinostat is a nonselective pan-histone deacetylase inhibitor that is being tested in preclinical and clinical studies, including for the treatment of pediatric medulloblastoma, which has a propensity for leptomeningeal spread and diffuse midline glioma, which can infiltrate into supratentorial brain regions. In this study, we examined the rate, extent, and spatial heterogeneity of panobinostat CNS distribution in mice. Transporter-deficient mouse studies show that panobinostat is a dual substrate of P-glycoprotein (P-gp) and breast cancer resistant protein (Bcrp), which are major efflux transporters expressed at the BBB. The CNS delivery of panobinostat was moderately limited by P-gp and Bcrp, and the unbound tissue-to-plasma partition coefficient of panobinostat was 0.32 and 0.21 in the brain and spinal cord in wild-type mice. In addition, following intravenous administration, panobinostat demonstrated heterogeneous distribution among brain regions, indicating that its efficacy would be influenced by tumor location or the presence and extent of leptomeningeal spread. Simulation using a compartmental BBB model suggests inadequate exposure of free panobinostat in the brain following a recommended oral dosing regimen in patients. Therefore, alternative approaches to CNS delivery may be necessary to have adequate exposure of free panobinostat for the treatment of a broad range of pediatric brain tumors. SIGNIFICANCE STATEMENT: This study shows that the central nervous system (CNS) penetration of panobinostat is limited by P-gp and Bcrp, and its efficacy may be limited by inadequate distribution to the tumor. Panobinostat has heterogeneous distribution into various brain regions, indicating that its efficacy might depend on the anatomical location of the tumors. These distributional parameters in the mouse CNS can inform both preclinical and clinical trial study design and may guide treatment for these devastating brain tumors in children.
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Affiliation(s)
- Wenqiu Zhang
- Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.)
| | - Ju-Hee Oh
- Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.)
| | - Wenjuan Zhang
- Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.)
| | - Sneha Rathi
- Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.)
| | - Jon D Larson
- Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.)
| | - Robert J Wechsler-Reya
- Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.)
| | - Rachael W Sirianni
- Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.)
| | - William F Elmquist
- Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota (Wenq.Z, J.-H.O., Wenj.Z., S.R., W.F.E.); Tumor Initiation & Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California (J.D.L.); Herbert Irving Comprehensive Cancer Center, Columbia University Medical, New York, New York (R.J.W.-R.); and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.)
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Maciejska A, Pomierny B, Krzyżanowska W, Starek-Świechowicz B, Skórkowska A, Budziszewska B. Mechanism of Microglial Cell Activation in the Benzophenone-3 Exposure Model. Neuroscience 2023; 533:63-76. [PMID: 37827357 DOI: 10.1016/j.neuroscience.2023.10.002] [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: 06/07/2023] [Revised: 09/19/2023] [Accepted: 10/05/2023] [Indexed: 10/14/2023]
Abstract
Benzophenone-3 (BP-3) is the most commonly used UV filter in cosmetics, which is absorbed through the skin and crosses the blood-brain barrier. This compound increases extracellular glutamate concentrations, lipid peroxidation, the number of microglia cells and induces process of apoptosis. The aim of this study was to determine the effect of BP-3 on the activation and polarization of microglial cells in the frontal cortex and hippocampus of adult male rats exposed to BP-3 prenatally and then for two weeks in adulthood. It has been found, that exposure to BP-3 reduced the expression of the marker of the M2 phenotype of glial cells in both examined brain structures. An increase in the CD86/CD206 microglial phenotype ratio, expression of transcription factor NFκB and activity of caspase-1 were observed only in the frontal cortex, whereas BP-3 increased the level of glucocorticoid receptors in the hippocampus. The in vitro study conducted in the primary culture of rat frontal cortical microglia cells showed that BP-3 increased the LPS-stimulated release of pro-inflammatory cytokines IL-1α, IL-1β, TNFα, but in cultures without LPS there was decreased IL-1α, IL-6 and TNFα production, while the IL-18 and IP-10 was elevated. The obtained results indicate that differences in the level of immunoactivation between the frontal cortex and the hippocampus may result from the action of this compound on glucocorticoid receptors. In turn, changes in cytokine production in microglial cells indicate that BP-3 aggravates the LPS-induced immunoactivation.
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Affiliation(s)
- Alicja Maciejska
- Department of Toxicological Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
| | - Bartosz Pomierny
- Department of Toxicological Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Weronika Krzyżanowska
- Department of Toxicological Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Beata Starek-Świechowicz
- Department of Toxicological Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Alicja Skórkowska
- Department of Toxicological Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Bogusława Budziszewska
- Department of Toxicological Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
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18
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Mir FA, Amanullah A, Jain BP, Hyderi Z, Gautam A. Neuroepigenetics of ageing and neurodegeneration-associated dementia: An updated review. Ageing Res Rev 2023; 91:102067. [PMID: 37689143 DOI: 10.1016/j.arr.2023.102067] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 09/01/2023] [Accepted: 09/06/2023] [Indexed: 09/11/2023]
Abstract
Gene expression is tremendously altered in the brain during memory acquisition, recall, and forgetfulness. However, non-genetic factors, including environmental elements, epigenetic changes, and lifestyle, have grabbed significant attention in recent years regarding the etiology of neurodegenerative diseases (NDD) and age-associated dementia. Epigenetic modifications are essential in regulating gene expression in all living organisms in a DNA sequence-independent manner. The genes implicated in ageing and NDD-related memory disorders are epigenetically regulated by processes such as DNA methylation, histone acetylation as well as messenger RNA editing machinery. The physiological and optimal state of the epigenome, especially within the CNS of humans, plays an intricate role in helping us adjust to the changing environment, and alterations in it cause many brain disorders, but the mechanisms behind it still need to be well understood. When fully understood, these epigenetic landscapes could act as vital targets for pharmacogenetic rescue strategies for treating several diseases, including neurodegeneration- and age-induced dementia. Keeping this objective in mind, this updated review summarises the epigenetic changes associated with age and neurodegeneration-associated dementia.
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Affiliation(s)
- Fayaz Ahmad Mir
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | | | - Zeeshan Hyderi
- Department of Biotechnology, Alagappa University, Karaikudi, India
| | - Akash Gautam
- Centre for Neural and Cognitive Sciences, University of Hyderabad, Hyderabad, India.
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Fila M, Pawlowska E, Szczepanska J, Blasiak J. Epigenetic Connections of the TRPA1 Ion Channel in Pain Transmission and Neurogenic Inflammation - a Therapeutic Perspective in Migraine? Mol Neurobiol 2023; 60:5578-5591. [PMID: 37326902 PMCID: PMC10471718 DOI: 10.1007/s12035-023-03428-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 06/05/2023] [Indexed: 06/17/2023]
Abstract
Persistent reprogramming of epigenetic pattern leads to changes in gene expression observed in many neurological disorders. Transient receptor potential cation channel subfamily A member 1 (TRPA1), a member of the TRP channels superfamily, is activated by many migraine triggers and expressed in trigeminal neurons and brain regions that are important in migraine pathogenesis. TRP channels change noxious stimuli into pain signals with the involvement of epigenetic regulation. The expression of the TRPA1 encoding gene, TRPA1, is modulated in pain-related syndromes by epigenetic alterations, including DNA methylation, histone modifications, and effects of non-coding RNAs: micro RNAs (miRNAs), long non-coding RNAs, and circular RNAs. TRPA1 may change epigenetic profile of many pain-related genes as it may modify enzymes responsible for epigenetic modifications and expression of non-coding RNAs. TRPA1 may induce the release of calcitonin gene related peptide (CGRP), from trigeminal neurons and dural tissue. Therefore, epigenetic regulation of TRPA1 may play a role in efficacy and safety of anti-migraine therapies targeting TRP channels and CGRP. TRPA1 is also involved in neurogenic inflammation, important in migraine pathogenesis. The fundamental role of TRPA1 in inflammatory pain transmission may be epigenetically regulated. In conclusion, epigenetic connections of TRPA1 may play a role in efficacy and safety of anti-migraine therapy targeting TRP channels or CGRP and they should be further explored for efficient and safe antimigraine treatment. This narrative/perspective review presents information on the structure and functions of TRPA1 as well as role of its epigenetic connections in pain transmission and potential in migraine therapy.
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Affiliation(s)
- Michal Fila
- Department of Developmental Neurology and Epileptology, Polish Mother's Memorial Hospital Research Institute, 93-338, Lodz, Poland
| | - Elzbieta Pawlowska
- Department of Pediatric Dentistry, Medical University of Lodz, 92-217, Lodz, Poland
| | - Joanna Szczepanska
- Department of Pediatric Dentistry, Medical University of Lodz, 92-217, Lodz, Poland
| | - Janusz Blasiak
- Department of Molecular Genetics, University of Lodz, 90-236, Lodz, Poland.
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Sarkisova KY, Gabova AV, Fedosova EA, Shatskova AB, Narkevich VB, Kudrin VS. Antidepressant and Anxiolytic Effects of L-Methionine in the WAG/Rij Rat Model of Depression Comorbid with Absence Epilepsy. Int J Mol Sci 2023; 24:12425. [PMID: 37569798 PMCID: PMC10419169 DOI: 10.3390/ijms241512425] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/29/2023] [Accepted: 08/01/2023] [Indexed: 08/13/2023] Open
Abstract
Depression is a severe and widespread psychiatric disease that often accompanies epilepsy. Antidepressant treatment of depression comorbid with epilepsy is a major concern due to the risk of seizure aggravation. SAMe, a universal methyl donor for DNA methylation and the synthesis of brain monoamines, is known to have high antidepressant activity. This study aimed to find out whether L-methionine (L-MET), a precursor of SAMe, can have antidepressant and/or anxiolytic effects in the WAG/Rij rat model of depression comorbid with absence epilepsy. The results indicate that L-MET reduces the level of anxiety and depression in WAG/Rij rats and suppresses associated epileptic seizures, in contrast to conventional antidepressant imipramine, which aggravates absence seizures. The antidepressant effect of L-MET was comparable with that of the conventional antidepressants imipramine and fluoxetine. However, the antidepressant profile of L-MET was more similar to imipramine than to fluoxetine. Taken together, our findings suggest that L-MET could serve as a promising new antidepressant drug with anxiolytic properties for the treatment of depression comorbid with absence epilepsy. Increases in the level of monoamines and their metabolites-DA, DOPAC, HVA, NA, and MHPG-in several brain structures, is suggested to be a neurochemical mechanism of the beneficial phenotypic effect of L-MET.
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Affiliation(s)
- Karine Yu. Sarkisova
- Institute of Higher Nervous Activity and Neurophysiology of Russian Academy of Sciences, Butlerova Str. 5A, Moscow 117485, Russia; (A.V.G.); (E.A.F.); (A.B.S.)
| | - Alexandra V. Gabova
- Institute of Higher Nervous Activity and Neurophysiology of Russian Academy of Sciences, Butlerova Str. 5A, Moscow 117485, Russia; (A.V.G.); (E.A.F.); (A.B.S.)
| | - Ekaterina A. Fedosova
- Institute of Higher Nervous Activity and Neurophysiology of Russian Academy of Sciences, Butlerova Str. 5A, Moscow 117485, Russia; (A.V.G.); (E.A.F.); (A.B.S.)
| | - Alla B. Shatskova
- Institute of Higher Nervous Activity and Neurophysiology of Russian Academy of Sciences, Butlerova Str. 5A, Moscow 117485, Russia; (A.V.G.); (E.A.F.); (A.B.S.)
| | - Victor B. Narkevich
- Federal State Budgetary Institution “Scientific Research Institute of Pharmacology named after V.V. Zakusov”, Baltiyskaya Str. 8, Moscow 125315, Russia; (V.B.N.); (V.S.K.)
| | - Vladimir S. Kudrin
- Federal State Budgetary Institution “Scientific Research Institute of Pharmacology named after V.V. Zakusov”, Baltiyskaya Str. 8, Moscow 125315, Russia; (V.B.N.); (V.S.K.)
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21
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Sun W, Xie G, Jiang X, Khaitovich P, Han D, Liu X. Epigenetic regulation of human-specific gene expression in the prefrontal cortex. BMC Biol 2023; 21:123. [PMID: 37226244 DOI: 10.1186/s12915-023-01612-3] [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: 11/04/2022] [Accepted: 05/03/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Changes in gene expression levels during brain development are thought to have played an important role in the evolution of human cognition. With the advent of high-throughput sequencing technologies, changes in brain developmental expression patterns, as well as human-specific brain gene expression, have been characterized. However, interpreting the origin of evolutionarily advanced cognition in human brains requires a deeper understanding of the regulation of gene expression, including the epigenomic context, along the primate genome. Here, we used chromatin immunoprecipitation sequencing (ChIP-seq) to measure the genome-wide profiles of histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 acetylation (H3K27ac), both of which are associated with transcriptional activation in the prefrontal cortex of humans, chimpanzees, and rhesus macaques. RESULTS We found a discrete functional association, in which H3K4me3HP gain was significantly associated with myelination assembly and signaling transmission, while H3K4me3HP loss played a vital role in synaptic activity. Moreover, H3K27acHP gain was enriched in interneuron and oligodendrocyte markers, and H3K27acHP loss was enriched in CA1 pyramidal neuron markers. Using strand-specific RNA sequencing (ssRNA-seq), we first demonstrated that approximately 7 and 2% of human-specific expressed genes were epigenetically marked by H3K4me3HP and H3K27acHP, respectively, providing robust support for causal involvement of histones in gene expression. We also revealed the co-activation role of epigenetic modification and transcription factors in human-specific transcriptome evolution. Mechanistically, histone-modifying enzymes at least partially contribute to an epigenetic disturbance among primates, especially for the H3K27ac epigenomic marker. In line with this, peaks enriched in the macaque lineage were found to be driven by upregulated acetyl enzymes. CONCLUSIONS Our results comprehensively elucidated a causal species-specific gene-histone-enzyme landscape in the prefrontal cortex and highlighted the regulatory interaction that drove transcriptional activation.
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Affiliation(s)
- Weifen Sun
- Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Academy of Forensic Science, Ministry of Justice, Shanghai, 200063, China
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, CAS, Shanghai, 200031, China
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Gangcai Xie
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, CAS, Shanghai, 200031, China
| | - Xi Jiang
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, CAS, Shanghai, 200031, China
| | - Philipp Khaitovich
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, CAS, Shanghai, 200031, China.
- Skolkovo Institute of Science and Technology, Moscow, 121205, Russia.
| | - Dingding Han
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, CAS, Shanghai, 200031, China.
- Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200062, China.
| | - Xiling Liu
- Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Service Platform, Academy of Forensic Science, Ministry of Justice, Shanghai, 200063, China.
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, CAS, Shanghai, 200031, China.
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22
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Pal D, Sahu P, Mishra AK, Hagelgans A, Sukocheva O. Histone Deacetylase Inhibitors as Cognitive Enhancers and Modifiers of Mood and Behavior. Curr Drug Targets 2023; 24:728-750. [PMID: 36475351 DOI: 10.2174/1389450124666221207090108] [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: 05/25/2022] [Revised: 09/29/2022] [Accepted: 10/10/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Epigenetic regulation of gene signalling is one of the fundamental molecular mechanisms for the generation and maintenance of cellular memory. Histone acetylation is a common epigenetic mechanism associated with increased gene transcription in the central nervous system (CNS). Stimulation of gene transcription by histone acetylation is important for the development of CNS-based long-term memory. Histone acetylation is a target for cognitive enhancement via the application of histone deacetylase (HDAC) inhibitors. The promising potential of HDAC inhibitors has been observed in the treatment of several neurodevelopmental and neurodegenerative diseases. OBJECTIVE This study assessed the current state of HDAC inhibition as an approach to cognitive enhancement and treatment of neurodegenerative diseases. Our analysis provides insights into the mechanism of action of HDAC inhibitors, associated epigenetic priming, and describes the therapeutic success and potential complications after unsupervised use of the inhibitors. RESULTS AND CONCLUSION Several chromatin-modifying enzymes play key roles in the regulation of cognitive processes. The importance of HDAC signaling in the brain is highlighted in this review. Recent advancements in the field of cognitive epigenetics are supported by the successful development of various HDAC inhibitors, demonstrating effective treatment of mood-associated disorders. The current review discusses the therapeutic potential of HDAC inhibition and observed complications after mood and cognitive enhancement therapies.
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Affiliation(s)
- Dilipkumar Pal
- Department of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, C.G., 495 009, India
| | - Pooja Sahu
- Department of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, C.G., 495 009, India
| | | | - Albert Hagelgans
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Olga Sukocheva
- College of Nursing and Health Sciences, Flinders University of South Australia, Bedford Park, 5042, SA, Australia
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23
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Mishra S, Raval M, Kachhawaha AS, Tiwari BS, Tiwari AK. Aging: Epigenetic modifications. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 197:171-209. [PMID: 37019592 DOI: 10.1016/bs.pmbts.2023.02.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/15/2023]
Abstract
Aging is one of the most complex and irreversible health conditions characterized by continuous decline in physical/mental activities that eventually poses an increased risk of several diseases and ultimately death. These conditions cannot be ignored by anyone but there are evidences that suggest that exercise, healthy diet and good routines may delay the Aging process significantly. Several studies have demonstrated that Epigenetics plays a key role in Aging and Aging-associated diseases through methylation of DNA, histone modification and non-coding RNA (ncRNA). Comprehension and relevant alterations in these epigenetic modifications can lead to new therapeutic avenues of age-delaying contrivances. These processes affect gene transcription, DNA replication and DNA repair, comprehending epigenetics as a key factor in understanding Aging and developing new avenues for delaying Aging, clinical advancements in ameliorating aging-related diseases and rejuvenating health. In the present article, we have described and advocated the epigenetic role in Aging and associated diseases.
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24
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Sarkisova K, van Luijtelaar G. The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities. IBRO Neurosci Rep 2022; 13:436-468. [PMID: 36386598 PMCID: PMC9649966 DOI: 10.1016/j.ibneur.2022.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/30/2022] [Accepted: 10/31/2022] [Indexed: 11/11/2022] Open
Abstract
This review discusses the long-term effects of early-life environment on epileptogenesis, epilepsy, and neuropsychiatric comorbidities with an emphasis on the absence epilepsy. The WAG/Rij rat strain is a well-validated genetic model of absence epilepsy with mild depression-like (dysthymia) comorbidity. Although pathologic phenotype in WAG/Rij rats is genetically determined, convincing evidence presented in this review suggests that the absence epilepsy and depression-like comorbidity in WAG/Rij rats may be governed by early-life events, such as prenatal drug exposure, early-life stress, neonatal maternal separation, neonatal handling, maternal care, environmental enrichment, neonatal sensory impairments, neonatal tactile stimulation, and maternal diet. The data, as presented here, indicate that some early environmental events can promote and accelerate the development of absence seizures and their neuropsychiatric comorbidities, while others may exert anti-epileptogenic and disease-modifying effects. The early environment can lead to phenotypic alterations in offspring due to epigenetic modifications of gene expression, which may have maladaptive consequences or represent a therapeutic value. Targeting DNA methylation with a maternal methyl-enriched diet during the perinatal period appears to be a new preventive epigenetic anti-absence therapy. A number of caveats related to the maternal methyl-enriched diet and prospects for future research are discussed.
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Affiliation(s)
- Karine Sarkisova
- Institute of Higher Nervous Activity and Neurophysiology of Russian Academy of Sciences, Butlerova str. 5a, Moscow 117485, Russia
| | - Gilles van Luijtelaar
- Donders Institute for Brain, Cognition, and Behavior, Donders Center for Cognition, Radboud University, Nijmegen, PO Box 9104, 6500 HE Nijmegen, the Netherlands
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25
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Baltacı NG, Toraman E, Akyüz M, Kalın ŞN, Budak H. Tip60/Kat5 may be a novel candidate histone acetyltransferase for the regulation of liver iron localization via acetylation. Biometals 2022; 35:1187-1197. [PMID: 35986817 DOI: 10.1007/s10534-022-00435-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 08/10/2022] [Indexed: 12/14/2022]
Abstract
Hepcidin (HAMP), an iron regulatory hormone synthesized by liver hepatocytes, works together with ferritin (FTH) and ferroportin (FPN) in regulating the storage, transport, and utilization of iron in the cell. Epigenetic mechanisms, especially acetylation, also play an important role in the regulation of iron metabolism. However, a target protein has not been mentioned yet. With this preliminary study, we investigated the effect of histone acetyltransferase TIP60 on the expression of HAMP, FTH, and FPN. In addition, how the depletion of Tip60, which regulates the circadian system, affects the daily expression of Hamp was examined at six Zeitgeber time (ZT) points. For this purpose, liver-specific Tip60 knockout mice (mutant) were produced with tamoxifen-inducible Cre/lox recombination and an iron overload model in mice was generated. While HAMP and FTH expressions decreased, FPN expression increased in the mutant group. Interestingly, there was no change in the iron content. A significant increase was observed in the expressions of HAMP, FTH, and FPN and total liver iron content in the liver tissue of the iron overload group. Since intracellular iron concentration is involved in regulating the circadian clock, temporal expression of Hamp was investigated in control and mutant groups at six ZT points. In the control group, Hamp accumulated in a circadian manner with maximal and minimal levels reaching around ZT16 and ZT8, respectively. In the mutant group, there was a significant reduction in Hamp expression in the light phase ZT0 and ZT4 and in the dark phase ZT16. These data are the first findings demonstrating a possible relationship between Tip60 and iron metabolism.
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Affiliation(s)
- Nurdan Gönül Baltacı
- Department of Molecular Biology and Genetics, Science Faculty, Atatürk University, 25240, Erzurum, Türkiye
| | - Emine Toraman
- Department of Molecular Biology and Genetics, Science Faculty, Atatürk University, 25240, Erzurum, Türkiye
| | - Mesut Akyüz
- Department of Molecular Biology and Genetics, Science Faculty, Atatürk University, 25240, Erzurum, Türkiye
- Department of Molecular Biology and Genetics, Science Faculty, Erzurum Technical University, Erzurum, Türkiye
| | - Şeyda Nur Kalın
- Department of Molecular Biology and Genetics, Science Faculty, Atatürk University, 25240, Erzurum, Türkiye
| | - Harun Budak
- Department of Molecular Biology and Genetics, Science Faculty, Atatürk University, 25240, Erzurum, Türkiye.
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26
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de Thonel A, Ahlskog JK, Daupin K, Dubreuil V, Berthelet J, Chaput C, Pires G, Leonetti C, Abane R, Barris LC, Leray I, Aalto AL, Naceri S, Cordonnier M, Benasolo C, Sanial M, Duchateau A, Vihervaara A, Puustinen MC, Miozzo F, Fergelot P, Lebigot É, Verloes A, Gressens P, Lacombe D, Gobbo J, Garrido C, Westerheide SD, David L, Petitjean M, Taboureau O, Rodrigues-Lima F, Passemard S, Sabéran-Djoneidi D, Nguyen L, Lancaster M, Sistonen L, Mezger V. CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder. Nat Commun 2022; 13:7002. [PMID: 36385105 PMCID: PMC9668993 DOI: 10.1038/s41467-022-34476-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 10/24/2022] [Indexed: 11/17/2022] Open
Abstract
Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.
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Affiliation(s)
- Aurélie de Thonel
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France.
| | - Johanna K Ahlskog
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Kevin Daupin
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Véronique Dubreuil
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Jérémy Berthelet
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, France
| | - Carole Chaput
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
- Ksilink, Strasbourg, France
| | - Geoffrey Pires
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Camille Leonetti
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Ryma Abane
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Lluís Cordón Barris
- Laboratory of Molecular Regulation of Neurogenesis, GIGA-Stem Cells and GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, CHU Sart Tilman, Liège, Belgium
| | - Isabelle Leray
- Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, F-44000, Nantes, France
| | - Anna L Aalto
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Sarah Naceri
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Marine Cordonnier
- INSERM, UMR1231, Laboratoire d'Excellence LipSTIC, Dijon, France
- University of Bourgogne Franche-Comté, Dijon, France
- Département d'Oncologie médicale, Centre Georges-François Leclerc, Dijon, France
| | - Carène Benasolo
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Matthieu Sanial
- CNRS, UMR 7592 Institut Jacques Monod, F-75205, Paris, France
| | - Agathe Duchateau
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
| | - Anniina Vihervaara
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- KTH Royal Institute of Technology, Stockholm, Sweden
| | - Mikael C Puustinen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Federico Miozzo
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France
- Neuroscience Institute-CNR (IN-CNR), Milan, Italy
| | - Patricia Fergelot
- Department of Medical Genetics, University Hospital of Bordeaux, Bordeaux, France and INSERM U1211, University of Bordeaux, Bordeaux, France
| | - Élise Lebigot
- Service de Biochimie-pharmaco-toxicologie, Hôpital Bicêtre, Hopitaux Universitaires Paris-Sud, 94270 Le Kremlin Bicêtre, Paris-Sud, France
| | - Alain Verloes
- Université de Paris, INSERM, NeuroDiderot, Robert-Debré Hospital, F-75019, Paris, France
- Genetics Department, AP-HP, Robert-Debré University Hospital, Paris, France
| | - Pierre Gressens
- Université de Paris, INSERM, NeuroDiderot, Robert-Debré Hospital, F-75019, Paris, France
| | - Didier Lacombe
- Department of Medical Genetics, University Hospital of Bordeaux, Bordeaux, France and INSERM U1211, University of Bordeaux, Bordeaux, France
| | - Jessica Gobbo
- INSERM, UMR1231, Laboratoire d'Excellence LipSTIC, Dijon, France
- University of Bourgogne Franche-Comté, Dijon, France
- Département d'Oncologie médicale, Centre Georges-François Leclerc, Dijon, France
| | - Carmen Garrido
- INSERM, UMR1231, Laboratoire d'Excellence LipSTIC, Dijon, France
- University of Bourgogne Franche-Comté, Dijon, France
- Département d'Oncologie médicale, Centre Georges-François Leclerc, Dijon, France
| | - Sandy D Westerheide
- Department of Cell Biology, Microbiology, and Molecular Biology, College of Arts and Sciences, University of South Florida, Tampa, FL, USA
| | - Laurent David
- Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, F-44000, Nantes, France
| | - Michel Petitjean
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, France
| | - Olivier Taboureau
- Université de Paris, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, France
| | | | - Sandrine Passemard
- Université de Paris, INSERM, NeuroDiderot, Robert-Debré Hospital, F-75019, Paris, France
| | | | - Laurent Nguyen
- Laboratory of Molecular Regulation of Neurogenesis, GIGA-Stem Cells and GIGA-Neurosciences, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, CHU Sart Tilman, Liège, Belgium
| | - Madeline Lancaster
- MRC Laboratory of Molecular Biology, Cambridge Biomedical, Campus, Cambridge, UK
| | - Lea Sistonen
- Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Valérie Mezger
- Université de Paris, CNRS, Epigenetics and Cell Fate, F-75013, Paris, France.
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27
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van Zundert B, Montecino M. Epigenetic Changes and Chromatin Reorganization in Brain Function: Lessons from Fear Memory Ensemble and Alzheimer’s Disease. Int J Mol Sci 2022; 23:ijms232012081. [PMID: 36292933 PMCID: PMC9602769 DOI: 10.3390/ijms232012081] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/03/2022] [Accepted: 10/05/2022] [Indexed: 11/16/2022] Open
Abstract
Healthy brain functioning in mammals requires a continuous fine-tuning of gene expression. Accumulating evidence over the last three decades demonstrates that epigenetic mechanisms and dynamic changes in chromatin organization are critical components during the control of gene transcription in neural cells. Recent genome-wide analyses show that the regulation of brain genes requires the contribution of both promoter and long-distance enhancer elements, which must functionally interact with upregulated gene expression in response to physiological cues. Hence, a deep comprehension of the mechanisms mediating these enhancer–promoter interactions (EPIs) is critical if we are to understand the processes associated with learning, memory and recall. Moreover, the onset and progression of several neurodegenerative diseases and neurological alterations are found to be strongly associated with changes in the components that support and/or modulate the dynamics of these EPIs. Here, we overview relevant discoveries in the field supporting the role of the chromatin organization and of specific epigenetic mechanisms during the control of gene transcription in neural cells from healthy mice subjected to the fear conditioning paradigm, a relevant model to study memory ensemble. Additionally, special consideration is dedicated to revising recent results generated by investigators working with animal models and human postmortem brain tissue to address how changes in the epigenome and chromatin architecture contribute to transcriptional dysregulation in Alzheimer’s disease, a widely studied neurodegenerative disease. We also discuss recent developments of potential new therapeutic strategies involving epigenetic editing and small chromatin-modifying molecules (or epidrugs).
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Affiliation(s)
- Brigitte van Zundert
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile
- CARE Biomedical Research Center, Santiago 8330005, Chile
- Correspondence: (B.v.Z.); (M.M.)
| | - Martin Montecino
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370186, Chile
- Millennium Institute Center for Genome Regulation CRG, Santiago 8370186, Chile
- Correspondence: (B.v.Z.); (M.M.)
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28
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Afridi R, Rahman MH, Suk K. Implications of glial metabolic dysregulation in the pathophysiology of neurodegenerative diseases. Neurobiol Dis 2022; 174:105874. [PMID: 36154877 DOI: 10.1016/j.nbd.2022.105874] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 08/28/2022] [Accepted: 09/21/2022] [Indexed: 11/16/2022] Open
Abstract
Glial cells are the most abundant cells of the brain, outnumbering neurons. These multifunctional cells are crucial for maintaining brain homeostasis by providing trophic and nutritional support to neurons, sculpting synapses, and providing an immune defense. Glia are highly plastic and undergo both structural and functional alterations in response to changes in the brain microenvironment. Glial phenotypes are intimately regulated by underlying metabolic machinery, which dictates the effector functions of these cells. Altered brain energy metabolism and chronic neuroinflammation are common features of several neurodegenerative diseases. Microglia and astrocytes are the major glial cells fueling the ongoing neuroinflammatory process, exacerbating neurodegeneration. Distinct metabolic perturbations in microglia and astrocytes, including altered carbohydrate, lipid, and amino acid metabolism have been documented in neurodegenerative diseases. These disturbances aggravate the neurodegenerative process by potentiating the inflammatory activation of glial cells. This review covers the recent advances in the molecular aspects of glial metabolic changes in the pathophysiology of neurodegenerative diseases. Finally, we discuss studies exploiting glial metabolism as a potential therapeutic avenue in neurodegenerative diseases.
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Affiliation(s)
- Ruqayya Afridi
- Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Md Habibur Rahman
- Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Kyoungho Suk
- Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea; Brain Science and Engineering Institute, Kyungpook National University, Daegu 41944, Republic of Korea.
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29
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Berger TC, Taubøll E, Heuser K. The potential role of DNA methylation as preventive treatment target of epileptogenesis. Front Cell Neurosci 2022; 16:931356. [PMID: 35936496 PMCID: PMC9353008 DOI: 10.3389/fncel.2022.931356] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/27/2022] [Indexed: 11/23/2022] Open
Abstract
Pharmacological therapy of epilepsy has so far been limited to symptomatic treatment aimed at neuronal targets, with the result of an unchanged high proportion of patients lacking seizure control. The dissection of the intricate pathological mechanisms that transform normal brain matter to a focus for epileptic seizures—the process of epileptogenesis—could yield targets for novel treatment strategies preventing the development or progression of epilepsy. While many pathological features of epileptogenesis have been identified, obvious shortcomings in drug development are now believed to be based on the lack of knowledge of molecular upstream mechanisms, such as DNA methylation (DNAm), and as well as a failure to recognize glial cell involvement in epileptogenesis. This article highlights the potential role of DNAm and related gene expression (GE) as a treatment target in epileptogenesis.
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Affiliation(s)
- Toni Christoph Berger
- Department of Neurology, Oslo University Hospital, Oslo, Norway
- *Correspondence: Toni Christoph Berger
| | - Erik Taubøll
- Department of Neurology, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Kjell Heuser
- Department of Neurology, Oslo University Hospital, Oslo, Norway
- Kjell Heuser
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30
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Epigenetic genes and epilepsy - emerging mechanisms and clinical applications. Nat Rev Neurol 2022; 18:530-543. [PMID: 35859062 DOI: 10.1038/s41582-022-00693-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/16/2022] [Indexed: 12/21/2022]
Abstract
An increasing number of epilepsies are being attributed to variants in genes with epigenetic functions. The products of these genes include factors that regulate the structure and function of chromatin and the placing, reading and removal of epigenetic marks, as well as other epigenetic processes. In this Review, we provide an overview of the various epigenetic processes, structuring our discussion around five function-based categories: DNA methylation, histone modifications, histone-DNA crosstalk, non-coding RNAs and chromatin remodelling. We provide background information on each category, describing the general mechanism by which each process leads to altered gene expression. We also highlight key clinical and mechanistic aspects, providing examples of genes that strongly associate with epilepsy within each class. We consider the practical applications of these findings, including tissue-based and biofluid-based diagnostics and precision medicine-based treatments. We conclude that variants in epigenetic genes are increasingly found to be causally involved in the epilepsies, with implications for disease mechanisms, treatments and diagnostics.
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Histone deacetylase 2 inhibitor valproic acid attenuates bisphenol A-induced liver pathology in male mice. Sci Rep 2022; 12:10258. [PMID: 35715448 PMCID: PMC9205966 DOI: 10.1038/s41598-022-12937-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 05/18/2022] [Indexed: 12/02/2022] Open
Abstract
Accumulating evidence indicates the role of endocrine disruptor bisphenol A (BPA) in many pathological conditions. Histone deacetylase (HDAC) inhibition has potential for the treatment of many diseases/abnormalities. Using a mouse BPA exposure model, this study investigated the hepatoprotective effects of the Food and Drug Administration–approved HDAC2 inhibitor valproic acid (VPA) against BPA-induced liver pathology. We randomly divided 30 adult male Swiss albino mice (8 weeks old; N = 6) into five groups: group 1, no treatment (sham control (SC)); group 2, only oral sterile corn oil (vehicle control (VC)); group 3, 4 mg/kg/day of oral BPA (single dose (BPA group)); group 4, 0.4% oral VPA (VPA group); and group 5, oral BPA + VPA (BPA + VPA group). At the age of 10 weeks, the mice were euthanized for biochemical and histological examinations. BPA promoted a significant decrease in the body weight (BW), an increase in the liver weight, and a significant increase in the levels of liver damage markers aspartate aminotransferase and alanine aminotransferase in the BPA group compared to SC, as well as pathological changes in liver tissue. We also found an increase in the rate of apoptosis among hepatocytes. In addition, BPA significantly increased the levels of oxidative stress indices, malondialdehyde, and protein carbonylation but decreased the levels of reduced glutathione (GSH) in the BPA group compared to SC. In contrast, treatment with the HDAC2 inhibitor VPA significantly attenuated liver pathology, oxidative stress, and apoptosis and also enhanced GSH levels in VPA group and BPA + VPA group. The HDAC2 inhibitor VPA protects mice against BPA-induced liver pathology, likely by inhibiting oxidative stress and enhancing the levels of antioxidant-reduced GSH.
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Sevoflurane inhibits histone acetylation and contributes to cognitive dysfunction by enhancing the expression of ANP32A in aging mice. Behav Brain Res 2022; 431:113949. [PMID: 35659510 DOI: 10.1016/j.bbr.2022.113949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 05/11/2022] [Accepted: 05/26/2022] [Indexed: 12/15/2022]
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Duan S, Li C, Gao Y, Meng P, Ji S, Xu Y, Mao Y, Wang H, Tian J. The tyrosine kinase inhibitor LPM4870108 impairs learning and memory and induces transcriptomic and gene‑specific DNA methylation changes in rats. Arch Toxicol 2022; 96:845-857. [PMID: 35098321 DOI: 10.1007/s00204-022-03226-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/12/2022] [Indexed: 11/02/2022]
Abstract
Tyrosine kinase inhibitors (TKIs), which have been developed and approved for cancer treatment in the last few years, are involved in synaptic plasticity of learning and memory. Epigenetic modifications also play crucial roles in the process of learning and memory, but its relationship with TKI-induced learning and memory impairment has not been investigated. We hypothesized that LPM4870108, an effective anti-cancer Trk inhibitor, might affect the learning and memory via epigenetic modifications. In this study, rats were orally administered with LPM4870108 (0, 1.25, 2.5, or 5.0 mg/kg) twice daily for 28 days, after which animals were subjected to a Morris water maze test. LPM4870108 exposure caused learning and memory impairments in this test in a dose-dependent manner and reduced the spine densities. Whole-genome transcriptomic analysis revealed significant differences in the patterns of hippocampal gene expression in LPM4870108-treated rats. These transcriptomic data were combined with next-generation bisulfite sequencing analysis, after which RT-PCR and pyrosequencing were conducted, revealing epigenetic alterations associated with genes (Snx8, Fgfr1, Dusp4, Vav2, and Satb2) known to regulate learning and memory. Increased mRNA and protein expression levels of hippocampal Dnmt1 and Dnmt3a were also observed in these rats. Overall, these data suggest that gene-specific alterations in patterns of DNA methylation can potentially contribute to the incidence of learning and memory deficits associated with exposure to LPM4870108.
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Affiliation(s)
- Sijin Duan
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, People's Republic of China
| | - Chunmei Li
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, People's Republic of China
| | - Yonglin Gao
- State Key Laboratory of Long-Acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai, 264003, People's Republic of China
- School of Life Science, Yantai University, Yantai, 264005, People's Republic of China
| | - Ping Meng
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, People's Republic of China
| | - Shengmin Ji
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, People's Republic of China
| | - Yangyang Xu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, People's Republic of China
| | - Yutong Mao
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, People's Republic of China
| | - Hongbo Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, People's Republic of China
| | - Jingwei Tian
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, People's Republic of China.
- State Key Laboratory of Long-Acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai, 264003, People's Republic of China.
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Sharma R, Sharma S, Thakur A, Singh A, Singh J, Nepali K, Liou JP. The Role of Epigenetic Mechanisms in Autoimmune, Neurodegenerative, Cardiovascular, and Imprinting Disorders. Mini Rev Med Chem 2022; 22:1977-2011. [PMID: 35176978 DOI: 10.2174/1389557522666220217103441] [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: 09/10/2021] [Revised: 10/01/2021] [Accepted: 11/11/2021] [Indexed: 11/22/2022]
Abstract
Epigenetic mutations like aberrant DNA methylation, histone modifications, or RNA silencing are found in a number of human diseases. This review article discusses the epigenetic mechanisms involved in neurodegenerative disorders, cardiovascular disorders, auto-immune disorder, and genomic imprinting disorders. In addition, emerging epigenetic therapeutic strategies for the treatment of such disorders are presented. Medicinal chemistry campaigns highlighting the efforts of the chemists invested towards the rational design of small molecule inhibitors have also been included. Pleasingly, several classes of epigenetic inhibitors, DNMT, HDAC, BET, HAT, and HMT inhibitors along with RNA based therapies have exhibited the potential to emerge as therapeutics in the longer run. It is quite hopeful that epigenetic modulator-based therapies will advance to clinical stage investigations by leaps and bounds.
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Affiliation(s)
- Ram Sharma
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Sachin Sharma
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Amandeep Thakur
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Arshdeep Singh
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Jagjeet Singh
- School of Pharmacy, University of Queensland, Brisbane, QLD, Australia.,Department of Pharmacy, Rayat-Bahara Group of Institutes, Hoshiarpur, India
| | - Kunal Nepali
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Jing Ping Liou
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
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35
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Shoubridge AP, Fourrier C, Choo JM, Proud CG, Sargeant TJ, Rogers GB. Gut Microbiome Regulation of Autophagic Flux and Neurodegenerative Disease Risks. Front Microbiol 2022; 12:817433. [PMID: 35003048 PMCID: PMC8733410 DOI: 10.3389/fmicb.2021.817433] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 12/02/2021] [Indexed: 11/21/2022] Open
Abstract
The gut microbiome-brain axis exerts considerable influence on the development and regulation of the central nervous system. Numerous pathways have been identified by which the gut microbiome communicates with the brain, falling largely into the two broad categories of neuronal innervation and immune-mediated mechanisms. We describe an additional route by which intestinal microbiology could mediate modifiable risk for neuropathology and neurodegeneration in particular. Autophagy, a ubiquitous cellular process involved in the prevention of cell damage and maintenance of effective cellular function, acts to clear and recycle cellular debris. In doing so, autophagy prevents the accumulation of toxic proteins and the development of neuroinflammation, both common features of dementia. Levels of autophagy are influenced by a range of extrinsic exposures, including nutrient deprivation, infection, and hypoxia. These relationships between exposures and rates of autophagy are likely to be mediated, as least in part, by the gut microbiome. For example, the suppression of histone acetylation by microbiome-derived short-chain fatty acids appears to be a major contributor to upregulation of autophagic function. We discuss the potential contribution of the microbiome-autophagy axis to neurological health and examine the potential of exploiting this link to predict and prevent neurodegenerative diseases.
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Affiliation(s)
- Andrew P Shoubridge
- Microbiome and Host Health, Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.,Infection and Immunity, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Célia Fourrier
- Lysosomal Health in Ageing, Hopwood Centre for Neurobiology, Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Jocelyn M Choo
- Microbiome and Host Health, Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.,Infection and Immunity, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Christopher G Proud
- Nutrition, Diabetes and Gut Health, Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.,School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
| | - Timothy J Sargeant
- Lysosomal Health in Ageing, Hopwood Centre for Neurobiology, Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Geraint B Rogers
- Microbiome and Host Health, Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.,Infection and Immunity, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
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36
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Bandeira IC, Giombelli L, Werlang IC, Abujamra AL, Secchi TL, Brondani R, Bragatti JA, Bizzi JWJ, Leistner-Segal S, Bianchin MM. Methylation of BDNF and SLC6A4 Gene Promoters in Brazilian Patients With Temporal Lobe Epilepsy Presenting or Not Psychiatric Comorbidities. Front Integr Neurosci 2021; 15:764742. [PMID: 34912196 PMCID: PMC8667271 DOI: 10.3389/fnint.2021.764742] [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: 08/25/2021] [Accepted: 10/25/2021] [Indexed: 01/09/2023] Open
Abstract
The relationship between epilepsy and psychiatric comorbidities has been recognized for centuries, but its pathophysiological mechanisms are still misunderstood. It is biologically plausible that genetic or epigenetic variations in genes that codify important neurotransmitters involved in epilepsy as well as in psychiatric disorders may influence the development of the latter in patients with epilepsy. However, this possibility remains poorly investigated. The aim of this study was to evaluate the methylation profile of the BDNF and SLC6A4, two genes importantly involved in neuroplasticity, in patients with temporal lobe epilepsy (TLE) regarding the development or not of psychiatric comorbidities. One hundred and thirty-nine patients with TLE, 90 females and 45 males, were included in the study. The mean age of patients was 44.0 (+12.0) years, and mean duration of epilepsy was 25.7 (+13.3) years. The Structured Clinical Interview for DSM-IV shows that 83 patients (59.7%) had neuropsychiatric disorders and 56 (40.3%) showed no psychiatric comorbidity. Mood disorders were the most common psychiatric disorder observed, being present in 64 (46.0%) of all 139 patients. Thirty-three (23.7%) patients showed anxiety disorders, 10 (7.2%) patients showed history of psychosis and 8 (5.8%) patients showed history of alcohol//drug abuse. Considering all 139 patients, 18 (12.9%) demonstrated methylation of the promoter region of both BDNF and SLC6A4 genes. A significant decreased methylation profile was observed only in TLE patients with mood disorders when compared with TLE patients without a history of mood disorders (O.R. = 3.45; 95% C.I. = 1.08–11.11; p = 0.04). A sub-analysis showed that TLE patients with major depressive disorder mostly account for this result (O.R. = 7.20; 95% C.I. = 1.01–56.16; p = 0.042). A logistic regression analysis showed that the independent factors associated with a history of depression in our TLE patients was female sex (O.R. = 2.30; 95% C.I. = 1.02–5.18; p = 0.044), not controlled seizures (O.R. = 2.51; 95% C.I. = 1.16–5.41; p = 0.019) and decreased methylation in BDNF and SLC6A4 genes (O.R. = 5.32; 95% C.I. = 1.14–25.00; p = 0.033). Our results suggest that BDNF or SLC6A4 genes profile methylation is independently associated with depressive disorders in patients with epilepsy. Further studies are necessary to clarify these matters.
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Affiliation(s)
- Isabel Cristina Bandeira
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Lucas Giombelli
- Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Isabel Cristina Werlang
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Ana Lucia Abujamra
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Thais Leite Secchi
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Rosane Brondani
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Division of Neurology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | | | | | - Sandra Leistner-Segal
- Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.,Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Marino Muxfeldt Bianchin
- Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Basic Research and Advanced Investigations in Neurosciences, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.,Division of Neurology, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.,Centro de Tratamento de Epilepsia Refratária (CETER), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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Miguel-Hidalgo JJ. Astroglia in the Vulnerability and Maintenance of Alcohol Use Disorders. ADVANCES IN NEUROBIOLOGY 2021; 26:255-279. [PMID: 34888838 DOI: 10.1007/978-3-030-77375-5_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Changes induced in the morphology and the multiplicity of functional roles played by astrocytes in brain regions critical to the establishment and maintenance of alcohol abuse suggest that they make an important contribution to the vulnerability to alcohol use disorders. The understanding of the relevant mechanisms accounting for that contribution is complicated by the fact that alcohol itself acts directly on astrocytes altering their metabolism, gene expression, and plasticity, so that the ultimate result is a complex interaction of various cellular pathways, including intracellular calcium regulation, neuroimmune responses, and regulation of neurotransmitter and gliotransmitter release and uptake. The recent years have seen a steady increase in the characterization of several of the relevant mechanisms, but much remains to be done for a full understanding of the astrocytes' contribution to the vulnerability to alcohol dependence and abuse and for using that knowledge in designing effective therapies for AUDs.
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Affiliation(s)
- José Javier Miguel-Hidalgo
- Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA.
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38
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Kameda T, Nakashima H, Takizawa T, Miura F, Ito T, Nakashima K, Imamura T. Neuronal activation modulates enhancer activity of genes for excitatory synaptogenesis through de novo DNA methylation. J Reprod Dev 2021; 67:369-379. [PMID: 34615840 PMCID: PMC8668374 DOI: 10.1262/jrd.2021-106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Post-mitotic neurons do exhibit DNA methylation changes, contrary to the longstanding belief that the epigenetic pattern in terminally differentiated cells is essentially unchanged. While
the mechanism and physiological significance of DNA demethylation in neurons have been extensively elucidated, the occurrence of de novo DNA methylation and its impacts have
been much less investigated. In the present study, we showed that neuronal activation induces de novo DNA methylation at enhancer regions, which can repress target genes in
primary cultured hippocampal neurons. The functional significance of this de novo DNA methylation was underpinned by the demonstration that inhibition of DNA
methyltransferase (DNMT) activity decreased neuronal activity-induced excitatory synaptogenesis. Overexpression of WW and C2 domain-containing 1 (Wwc1), a representative
target gene of de novo DNA methylation, could phenocopy this DNMT inhibition-induced decrease in synaptogenesis. We found that both DNMT1 and DNMT3a were required for
neuronal activity-induced de novo DNA methylation of the Wwc1 enhancer. Taken together, we concluded that neuronal activity-induced de novo
DNA methylation that affects gene expression has an impact on neuronal physiology that is comparable to that of DNA demethylation. Since the different requirements of DNMTs for germ cell and
embryonic development are known, our findings also have considerable implications for future studies on epigenomics in the field of reproductive biology.
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Affiliation(s)
- Tomonori Kameda
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.,Laboratory of Molecular and Cellular Physiology, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8526, Japan
| | - Hideyuki Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Takumi Takizawa
- Department of Pediatrics, Graduate School of Medicine, Gunma University, Gunma 371-8511, Japan
| | - Fumihito Miura
- Department of Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Takashi Ito
- Department of Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kinichi Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Takuya Imamura
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.,Laboratory of Molecular and Cellular Physiology, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8526, Japan
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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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Sun YM, Shen Y, Huang H, Liu Q, Chen C, Ma LH, Wan J, Sun YY, Zhou CH, Wu YQ. Downregulated SIRT1 in the CeA is involved in chronic pain-depression comorbidity. Brain Res Bull 2021; 174:339-348. [PMID: 34245841 DOI: 10.1016/j.brainresbull.2021.07.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 06/27/2021] [Accepted: 07/05/2021] [Indexed: 12/11/2022]
Abstract
Comorbid chronic pain and depression are increasingly becoming a concerning public problem, but the underlying mechanisms remain unclear. Here, we demonstrate that pain-related depression-like behaviors are induced in a rat model of chronic constriction injury (CCI). Using this model, we found that chronic neuropathic pain decreased the activity and expression of sirtuin 1 (SIRT1, an NAD+-dependent deacetylase) in the central nucleus of the amygdala (CeA). In addition, the pharmacologic activation of SIRT1 in the CeA could alleviate the depression-like behaviors associated with chronic pain while relieving sensory pain. Accordingly, adeno-associated virus (AAV)-mediated SIRT1 overexpression in the CeA produced a positive effect on the easement of chronic pain and comorbid depression. Taken together, these findings highlight the role of SIRT1 in the CeA in chronic pain and depression states and reveal that the upregulation of SIRT1 may be a potential therapy for the treatment of pain-depression comorbidities.
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Affiliation(s)
- Yi-Man Sun
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, PR China
| | - Ying Shen
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, PR China
| | - Hui Huang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, PR China
| | - Qiang Liu
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, PR China
| | - Chen Chen
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, PR China
| | - Lin-Hui Ma
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, PR China
| | - Jie Wan
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, PR China
| | - Yin-Ying Sun
- School of Anesthesiology, Xuzhou Medical University, Xuzhou, PR China
| | - Cheng-Hua Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, PR China.
| | - Yu-Qing Wu
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, PR China.
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41
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Ribeiro ACR, Jahr FM, Hawkins E, Kronfol MM, Younis RM, McClay JL, Deshpande LS. Epigenetic histone acetylation and Bdnf dysregulation in the hippocampus of rats exposed to repeated, low-dose diisopropylfluorophosphate. Life Sci 2021; 281:119765. [PMID: 34186043 DOI: 10.1016/j.lfs.2021.119765] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 06/08/2021] [Accepted: 06/21/2021] [Indexed: 10/21/2022]
Abstract
AIMS Deployment-related exposures to organophosphate (OP) compounds are implicated for Gulf War Illness (GWI) development in First GW veterans. However, reasons for the persistence of GWI are not fully understood. Epigenetic modifications to chromatin are regulatory mechanisms that can adaptively or maladaptively respond to external stimuli. These include DNA methylation and histone acetylation. DNA methylation changes have been reported in GWI but the role of histone acetylation in GWI has been less explored, despite its importance as an epigenetic mechanism for neurological disorders. MAIN METHODS Male Sprague-Dawley rats were exposed to OP diisopropyl fluorophosphate (DFP, 0.5 mg/kg s.c., 5-d) and 6-m later brains were dissected for hippocampus. Western blotting, activity assays and chromatin immunoprecipitation (ChIP) were utilized for epigenetic analyses. Behavior was assessed using the Forced Swim Test (FST) and the Elevated Plus Maze (EPM). KEY FINDINGS We observed a significant upregulation in HDAC1 protein along with a significant increase in HDAC enzyme activity in the hippocampus of DFP rats. A locus-specific ChIP study revealed decreases in H3K9ac at the brain derived neurotrophic factor (Bdnf) promoter IV coupled with a significant decrease in BDNF protein in DFP rat hippocampus. Treatment with HDAC inhibitor valproic acid reduced HDAC activity and decreased the FST immobility time in DFP rats. SIGNIFICANCE Our research suggests that epigenetic alterations to histone acetylation pathways and decreased BDNF expression could represent novel mechanisms for GWI symptomatology and may provide new targets for developing effective drugs for GWI treatment.
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Affiliation(s)
- Ana C R Ribeiro
- Department of Neurology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Fay M Jahr
- Department of Pharmacotherapy & Outcome Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
| | - Elisa Hawkins
- Department of Neurology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Mohamad M Kronfol
- Department of Pharmacotherapy & Outcome Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
| | - Rabha M Younis
- Department of Pharmacotherapy & Outcome Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
| | - Joseph L McClay
- Department of Pharmacotherapy & Outcome Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
| | - Laxmikant S Deshpande
- Department of Neurology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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42
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Kyrke-Smith M, Volk LJ, Cooke SF, Bear MF, Huganir RL, Shepherd JD. The Immediate Early Gene Arc Is Not Required for Hippocampal Long-Term Potentiation. J Neurosci 2021; 41:4202-4211. [PMID: 33833081 PMCID: PMC8143205 DOI: 10.1523/jneurosci.0008-20.2021] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 11/21/2022] Open
Abstract
Memory consolidation is thought to occur through protein synthesis-dependent synaptic plasticity mechanisms such as long-term potentiation (LTP). Dynamic changes in gene expression and epigenetic modifications underlie the maintenance of LTP. Similar mechanisms may mediate the storage of memory. Key plasticity genes, such as the immediate early gene Arc, are induced by learning and by LTP induction. Mice that lack Arc have severe deficits in memory consolidation, and Arc has been implicated in numerous other forms of synaptic plasticity, including long-term depression and cell-to-cell signaling. Here, we take a comprehensive approach to determine if Arc is necessary for hippocampal LTP in male and female mice. Using a variety of Arc knock-out (KO) lines, we found that germline Arc KO mice show no deficits in CA1 LTP induced by high-frequency stimulation and enhanced LTP induced by theta-burst stimulation. Temporally restricting the removal of Arc to adult animals and spatially restricting it to the CA1 using Arc conditional KO mice did not have an effect on any form of LTP. Similarly, acute application of Arc antisense oligodeoxynucleotides had no effect on hippocampal CA1 LTP. Finally, the maintenance of in vivo LTP in the dentate gyrus of Arc KO mice was normal. We conclude that Arc is not necessary for hippocampal LTP and may mediate memory consolidation through alternative mechanisms.SIGNIFICANCE STATEMENT The immediate early gene Arc is critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modeled experimentally by induction of LTP, which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and may regulate memory storage through alternative mechanisms.
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Affiliation(s)
| | - Lenora J Volk
- Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205
- Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390
| | - Samuel F Cooke
- The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
- Department of Basic and Clinical Neurosciences, King's College London, London, WC2R 2LS, United Kingdom
- MRC Centre for Neurodevelopmental Disorders, King's College London, London, SE1 1UL, United Kingdom
| | - Mark F Bear
- The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
| | - Richard L Huganir
- Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205
| | - Jason D Shepherd
- Department of Neurobiology, University of Utah, Salt Lake City, Utah 84112
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43
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Rasheed M, Liang J, Wang C, Deng Y, Chen Z. Epigenetic Regulation of Neuroinflammation in Parkinson's Disease. Int J Mol Sci 2021; 22:4956. [PMID: 34066949 PMCID: PMC8125491 DOI: 10.3390/ijms22094956] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 02/08/2023] Open
Abstract
Neuroinflammation is one of the most significant factors involved in the initiation and progression of Parkinson's disease. PD is a neurodegenerative disorder with a motor disability linked with various complex and diversified risk factors. These factors trigger myriads of cellular and molecular processes, such as misfolding defective proteins, oxidative stress, mitochondrial dysfunction, and neurotoxic substances that induce selective neurodegeneration of dopamine neurons. This neuronal damage activates the neuronal immune system, including glial cells and inflammatory cytokines, to trigger neuroinflammation. The transition of acute to chronic neuroinflammation enhances the susceptibility of inflammation-induced dopaminergic neuron damage, forming a vicious cycle and prompting an individual to PD development. Epigenetic mechanisms recently have been at the forefront of the regulation of neuroinflammatory factors in PD, proposing a new dawn for breaking this vicious cycle. This review examined the core epigenetic mechanisms involved in the activation and phenotypic transformation of glial cells mediated neuroinflammation in PD. We found that epigenetic mechanisms do not work independently, despite being coordinated with each other to activate neuroinflammatory pathways. In this regard, we attempted to find the synergic correlation and contribution of these epigenetic modifications with various neuroinflammatory pathways to broaden the canvas of underlying pathological mechanisms involved in PD development. Moreover, this study highlighted the dual characteristics (neuroprotective/neurotoxic) of these epigenetic marks, which may counteract PD pathogenesis and make them potential candidates for devising future PD diagnosis and treatment.
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Affiliation(s)
| | | | | | | | - Zixuan Chen
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (J.L.); (C.W.); (Y.D.)
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44
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Cozzolino F, Iacobucci I, Monaco V, Monti M. Protein-DNA/RNA Interactions: An Overview of Investigation Methods in the -Omics Era. J Proteome Res 2021; 20:3018-3030. [PMID: 33961438 PMCID: PMC8280749 DOI: 10.1021/acs.jproteome.1c00074] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
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The fields of application
of functional proteomics are not limited
to the study of protein–protein interactions; they also extend
to those involving protein complexes that bind DNA or RNA. These interactions
affect fundamental processes such as replication, transcription, and
repair in the case of DNA, as well as transport, translation, splicing,
and silencing in the case of RNA. Analytical or preparative experimental
approaches, both in vivo and in vitro, have been developed to isolate and identify DNA/RNA binding proteins
by exploiting the advantage of the affinity shown by these proteins
toward a specific oligonucleotide sequence. The present review proposes
an overview of the approaches most commonly employed in proteomics
applications for the identification of nucleic acid-binding proteins,
such as affinity purification (AP) protocols, EMSA, chromatin purification
methods, and CRISPR-based chromatin affinity purification, which are
generally associated with mass spectrometry methodologies for the
unbiased protein identification.
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Affiliation(s)
- Flora Cozzolino
- Department of Chemical Sciences, University Federico II of Naples, Strada Comunale Cinthia, 26, 80126 Naples, Italy.,CEINGE Advanced Biotechnologies, Via G. Salvatore 486, 80145 Naples, Italy
| | - Ilaria Iacobucci
- Department of Chemical Sciences, University Federico II of Naples, Strada Comunale Cinthia, 26, 80126 Naples, Italy.,CEINGE Advanced Biotechnologies, Via G. Salvatore 486, 80145 Naples, Italy
| | - Vittoria Monaco
- CEINGE Advanced Biotechnologies, Via G. Salvatore 486, 80145 Naples, Italy.,Interuniversity Consortium National Institute of Biostructures and Biosystems (INBB), Viale Medaglie d'Oro, 305-00136 Rome, Italy
| | - Maria Monti
- Department of Chemical Sciences, University Federico II of Naples, Strada Comunale Cinthia, 26, 80126 Naples, Italy.,CEINGE Advanced Biotechnologies, Via G. Salvatore 486, 80145 Naples, Italy
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45
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Epigenetic upregulation of acid-sensing ion channel 1 contributes to gastric hypersensitivity in adult offspring rats with prenatal maternal stress. Pain 2021; 161:989-1004. [PMID: 31895269 DOI: 10.1097/j.pain.0000000000001785] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Functional dyspepsia is a common functional gastrointestinal disorder. Gastric hypersensitivity (GHS) is a hallmark of this disorder, but the cellular mechanisms remain largely unknown. Stressors during gestational period could have effects on the offspring's tissue structure and function, which may predispose to gastrointestinal diseases. The aim of this study was to test whether prenatal maternal stress (PMS) induces GHS and to investigate role of acid-sensing ion channel (ASIC)/nuclear factor-κB (NF-κB) signaling by examining Asic1 methylation status in adult offspring rats. Gastric hypersensitivity in response to gastric distension was examined by electromyography recordings. Changes in neuronal excitability were determined by whole-cell patch-clamp recording techniques. Demethylation of CpG islands of Asic1 was determined by methylation-specific PCR and bisulfite sequencing assay. Prenatal maternal stress produced GHS in adult offspring rats. Treatment with amiloride, an inhibitor of ASICs, significantly attenuated GHS and reversed hyperexcitability of gastric-specific dorsal root ganglion (DRG) neurons labeled by the dye DiI. Expression of ASIC1 and NF-κBp65 was markedly enhanced in T7 to T10 DRGs. Furthermore, PMS led to a significant demethylation of CpG islands in the Asic1 promoter. A chromatin immunoprecipitation assay showed that PMS also enhanced the ability of NF-κBp65 to bind the promoter of Asic1 gene. Blockade of NF-κB using lentiviral-p65shRNA reversed upregulation of ASIC1 expression, GHS, and the hyperexcitability of DRG neurons. These data suggest that upregulation of ASIC1 expression is attributed to Asic1 promoter DNA demethylation and NF-κB activation, and that the enhanced interaction of the Asic1 and NF-κBp65 contributes to GHS induced by PMS.
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46
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Lanshakov DA, Sukhareva EV, Bulygina VV, Bannova AV, Shaburova EV, Kalinina TS. Single neonatal dexamethasone administration has long-lasting outcome on depressive-like behaviour, Bdnf, Nt-3, p75ngfr and sorting receptors (SorCS1-3) stress reactive expression. Sci Rep 2021; 11:8092. [PMID: 33854153 PMCID: PMC8046778 DOI: 10.1038/s41598-021-87652-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 03/31/2021] [Indexed: 12/22/2022] Open
Abstract
Elevated glucocorticoid level in the early postnatal period is associated with glucocorticoid therapy prescribed at preterm delivery most often has severe long-lasting neurodevelopmental and behavioural effects. Detailed molecular mechanisms of such programming action of antenatal glucocorticoids on behaviour are still poorly understood. To address this question we studied neurotrophins: Bdnf, Nt-3, Ngf and their receptors: p75ngfr, Sorcs3 expression changes after subcutaneous dexamethasone (DEX) 0.2 mg/kg injection to P2 rat pups. Neurotrophins expression level was studied in the hippocampus (HPC). Disturbances in these brain regions have been implicated in the emergence of multiple psychopathologies. p75ngfr and Sorcs3 expression was studied in the brainstem—region where monoamine neurons are located. Immunohistochemically P75NTR protein level changes after DEX were investigated in the brainstem Locus Coereleus norepinephrine neurons (NE). In the first hours after DEX administration elevation of neurotrophins expression in HPC and decline of receptor’s expression in the NE brainstem neurons were observed. Another critical time point during maturation is adolescence. Impact of elevated glucocorticoid level in the neonatal period and unpredictable stress (CMUS) at the end of adolescence on depressive-like behaviour was studied. Single neonatal DEX injection leads to decrease in depressive-like behaviour, observed in FST, independently from chronic stress. Neonatal DEX administration decreased Ntf3 and SorCS1 expression in the brainstem. Also Bdnf mRNA level in the brainstem of these animals didn’t decrease after FST. CMUS at the end of adolescence changed p75ngfr and SorCS3 expression in the brainstem in the animals that received single neonatal DEX administration.
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Affiliation(s)
- D A Lanshakov
- Laboratory of Postgenomics Neurobiology, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian Federation, 630090.
| | - E V Sukhareva
- Functional Neurogenomics Laboratory, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian Federation, 630090.,Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russian Federation, 630090
| | - V V Bulygina
- Functional Neurogenomics Laboratory, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian Federation, 630090
| | - A V Bannova
- Functional Neurogenomics Laboratory, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian Federation, 630090
| | - E V Shaburova
- Functional Neurogenomics Laboratory, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian Federation, 630090.,Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russian Federation, 630090
| | - T S Kalinina
- Functional Neurogenomics Laboratory, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian Federation, 630090.,Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russian Federation, 630090
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Pulya S, Mahale A, Bobde Y, Routholla G, Patel T, Swati, Biswas S, Sharma V, Kulkarni OP, Ghosh B. PT3: A Novel Benzamide Class Histone Deacetylase 3 Inhibitor Improves Learning and Memory in Novel Object Recognition Mouse Model. ACS Chem Neurosci 2021; 12:883-892. [PMID: 33577290 DOI: 10.1021/acschemneuro.0c00721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The importance of HDAC3 in transcriptional regulation of genes associated with long-term memory is well established. Here, we report a novel HDAC3 inhibitor, PT3, with an excellent blood-brain barrier permeability and ability to enhance long-term memory in mouse model of novel object recognition (NOR). PT3 exhibited higher selectivity for HDAC3 over HDAC1, HDAC6, and HDAC8 compared to the reference compound CI994. PT3 has significant distribution into the brain tissue with Cmax at 0.5 h and t1/2 of 2.5 h. Treatment with PT3 significantly improved the discrimination index in C57/BL6 mice in the NOR model. Brain tissue analysis of mice treated with PT3 for NOR test showed significant increase in H3K9 acetylation in hippocampus. Gene expression analysis by RT-qPCR of the hippocampus tissue revealed upregulation of CREB 1, BDNF, TRKB, Nr4a2, c-fos, PKA, GAP 43, PSD 95 and MMP9 expression in mice treated with PT3. Similar to the phenotype observed in the in vivo experiment, we found upregulation of H3K9 acetylation, CREB 1, BDNF, TRKB, Nr4a2, c-fos, PKA, GAP 43 and MMP9 expression in mouse neuronal (N2A) cells treated with PT3. Thus, our preclinical studies identify PT3 as a potential HDAC3 selective inhibitor that crosses the blood-brain barrier and improves the long-term memory formation in C57/BL6 mice. We propose PT3 as a candidate with therapeutic potential to treat age-related memory loss as well as other disorders with declined memory function like Alzheimer's disease.
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Affiliation(s)
- Sravani Pulya
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, India
| | - Ashutosh Mahale
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, India
| | - Yamini Bobde
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, India
| | - Ganesh Routholla
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, India
| | - Tarun Patel
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, India
| | - Swati
- Department of Biological Science, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, India
| | - Swati Biswas
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, India
| | - Vivek Sharma
- Department of Biological Science, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, India
| | - Onkar P. Kulkarni
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, India
| | - Balaram Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad 500078, India
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48
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Strepkos D, Markouli M, Klonou A, Papavassiliou AG, Piperi C. Histone Methyltransferase SETDB1: A Common Denominator of Tumorigenesis with Therapeutic Potential. Cancer Res 2021; 81:525-534. [PMID: 33115801 DOI: 10.1158/0008-5472.can-20-2906] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/06/2020] [Accepted: 10/23/2020] [Indexed: 11/16/2022]
Abstract
Epigenetic regulation of gene expression has been ultimately linked to cancer development, with posttranslational histone modifications representing attractive targets for disease monitoring and therapy. Emerging data have demonstrated histone lysine (K) methylation by methyltransferase SETDB1 as a common denominator of gene regulation in several cancer types. SETDB1 reversibly catalyzes the di- and trimethylation of histone 3 (H3) K9 in euchromatic regions of chromosomes, inhibiting gene transcription within these regions and promoting a switch from euchromatic to heterochromatic states. Recent studies have implicated aberrant SETDB1 activity in the development of various types of cancers, including brain, head and neck, lung, breast, gastrointestinal, ovarian, endometrial and prostate cancer, mesothelioma, melanoma, leukemias, and osteosarcoma. Although its role has not been fully elucidated in every case, most data point toward a pro-oncogenic potential of SETDB1 via the downregulation of critical tumor-suppressive genes. Less commonly, however, SETDB1 can also acquire a tumor-suppressive role, depending on cancer type and stage. Here we provide an updated overview of the cellular and molecular effects underlying SETDB1 activity in cancer development and progression along with current targeting strategies in different cancer types, with promising effects either as a standalone therapy or in conjunction with other therapeutic agents.
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Affiliation(s)
- Dimitrios Strepkos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Mariam Markouli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexia Klonou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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49
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"Omics" in traumatic brain injury: novel approaches to a complex disease. Acta Neurochir (Wien) 2021; 163:2581-2594. [PMID: 34273044 PMCID: PMC8357753 DOI: 10.1007/s00701-021-04928-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/23/2021] [Indexed: 11/12/2022]
Abstract
BACKGROUND To date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete understanding of the vast complexity of the biological cascades and failure to appreciate the diversity of secondary injury mechanisms in TBI. In recent years, techniques for high-throughput characterization and quantification of biological molecules that include genomics, proteomics, and metabolomics have evolved and referred to as omics. METHODS In this narrative review, we highlight how omics technology can be applied to potentiate diagnostics and prognostication as well as to advance our understanding of injury mechanisms in TBI. RESULTS The omics platforms provide possibilities to study function, dynamics, and alterations of molecular pathways of normal and TBI disease states. Through advanced bioinformatics, large datasets of molecular information from small biological samples can be analyzed in detail and provide valuable knowledge of pathophysiological mechanisms, to include in prognostic modeling when connected to clinically relevant data. In such a complex disease as TBI, omics enables broad categories of studies from gene compositions associated with susceptibility to secondary injury or poor outcome, to potential alterations in metabolites following TBI. CONCLUSION The field of omics in TBI research is rapidly evolving. The recent data and novel methods reviewed herein may form the basis for improved precision medicine approaches, development of pharmacological approaches, and individualization of therapeutic efforts by implementing mathematical "big data" predictive modeling in the near future.
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50
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Kyrke-Smith M, Logan B, Abraham WC, Williams JM. Bilateral histone deacetylase 1 and 2 activity and enrichment at unique genes following induction of long-term potentiation in vivo. Hippocampus 2020; 31:389-407. [PMID: 33378103 DOI: 10.1002/hipo.23297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 12/15/2020] [Accepted: 12/19/2020] [Indexed: 11/10/2022]
Abstract
Long-term potentiation (LTP) is a synaptic plasticity mechanism critical to long-term memory. LTP induced in vivo is characterized by altered transcriptional activity, including a period of upregulation of gene expression which is followed by a later dominant downregulation. This temporal shift to downregulated gene expression is predicted to be partly mediated by epigenetic inhibitors of gene expression, such as histone deacetylases (HDACs). Further, pharmacological inhibitors of HDAC activity have previously been shown to enhance LTP persistence in vitro. To explore the contribution of HDACs to the persistence of LTP in vivo, we examined HDAC1 and HDAC2 activity over a 24 hr period following unilateral LTP induction in the dentate gyrus of freely moving rats. Surprisingly, we found significant changes in HDAC1 and HDAC2 activity in both the stimulated as well as the unstimulated hemispheres, with the largest increase in activity occurring bilaterally, 20 min after LTP stimulation. During this time point of heightened activity, chromatin immunoprecipitation assays showed that both HDAC1 and HDAC2 were enriched at distinct sets of genes within each hemispheres. Further, the HDAC inhibitor Trichostatin A enhanced an intermediate phase of LTP lasting days, which has not previously been associated with altered transcription. The inhibitor had no effect on the persistence of LTP lasting weeks. Together, these data suggest that HDAC activity early after the induction of LTP may negatively regulate plasticity-related gene expression that is involved in the initial stabilization of LTP, but not its long-term maintenance.
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Affiliation(s)
- Madeleine Kyrke-Smith
- Department of Anatomy, University of Otago, Dunedin, New Zealand.,Department of Psychology, University of Otago, Dunedin, New Zealand
| | - Barbara Logan
- Department of Anatomy, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, Brain Research New Zealand-Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
| | - Wickliffe C Abraham
- Department of Anatomy, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, Brain Research New Zealand-Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
| | - Joanna M Williams
- Department of Anatomy, University of Otago, Dunedin, New Zealand.,Department of Psychology, University of Otago, Dunedin, New Zealand.,Brain Health Research Centre, Brain Research New Zealand-Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand
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