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Rack S, Patel K, Heathcote E, Mistry H, Betts G, Harrington K, Metcalf R. KDM6A, ARID1A and SETD2 loss-of-function mutations as prognostic biomarkers and their association with sites of metastatic progression in locally-advanced, recurrent or metastatic adenoid cystic carcinoma. Oral Oncol 2025; 166:107229. [PMID: 40381467 DOI: 10.1016/j.oraloncology.2025.107229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/13/2025] [Accepted: 02/23/2025] [Indexed: 05/20/2025]
Abstract
OBJECTIVES Recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) is typically slow growing however, some patients have more rapid progression. We sought to classify mutations in chromatin regulating genes in ACC to determine the impact of chromatin regulatory disfunction on clinical outcomes. MATERIALS AND METHODS Matched clinical-genomic data from 271 pts with non-resectable or R/M ACC were included in this study. 132 pts were recruited locally. 139 ACC pts were included from cBioPortal for analysis. Mutations were classified as pathogenic using standardised bioinformatic pipelines. Analyses was performed to determine the impact of one or more mutations on overall survival from recurrence (OSr) and site of metastases. RESULTS KDM6A mutations were seen in 12 % of patients, followed by ARID1A 9 %, EP300 6 %, CREBBP 5 %, KMT2D 5 %, SETD2 2.6 %, an KMT2C 1.8 %. While 15 % of patients harboured activating NOTCH1/2 mutations, which co-occurred with mutations in KDM6A, ARID1A, and CREBBP. NOTCH activation (8.4 v 2.3 years, p= <0.005), KDM6A (6.6 v 4.6 years, p = 0.008) and SETD2 (5.9 v 3.8 years, p = 0.04) mutations were associated with worse OSr. In NOTCH wild-type patients, median OSr for KDM6A 9.2 v 4.8 years (p = 0.07) and SETD2 was 9.8 v 3.2 years (p = 0.04). KDM6A (OR 4.5, 95 % CI 1.7-13.2, p = 0.002) mutations were significantly associated with bone metastasises and ARID1A mutations were associated with bone (OR 3.5, 95 % CI 1.2-11.8, p = 0.025) and liver (OR 3.0, 95 % CI 1.0-9.1, p = 0.053) in NOTCH wild-type patients. CONCLUSIONS ARID1A, KDM6A and SETD2 loss of function mutations negatively impact clinical outcomes in R/M-ACC irrespective of NOTCH status.
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Affiliation(s)
- Sam Rack
- The Christie NHS Foundation Trust, Manchester, UK
| | - Karan Patel
- The Christie NHS Foundation Trust, Manchester, UK
| | | | | | - Guy Betts
- Manchester University NHS Foundation Trust, Manchester, UK
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Tang S, Wang Q, Wang Z, Cai L, Pan D, Li J, Chen Q, Zhou Y, Shen YQ. NSD1 mutation status determines metabolic inhibitor sensitivity in head and neck squamous cell carcinomas by regulating mitochondrial respiration. J Pathol 2025. [PMID: 40371884 DOI: 10.1002/path.6430] [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: 12/12/2024] [Revised: 01/20/2025] [Accepted: 03/24/2025] [Indexed: 05/16/2025]
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are the most common malignant tumors in the head and neck region, characterized by a high recurrence rate and early metastasis. Despite advances in treatment, patient outcomes and prognosis remain poor, highlighting the urgent need for new therapeutic strategies. Recent research has increasingly focused on targeting glucose metabolism as a therapeutic strategy for cancer, revealing multiple promising targets and potential drugs. However, the metabolic heterogeneity among tumors leads to variable sensitivity to metabolic inhibitors in different patients, limiting their clinical utility. In this study, we employed bioinformatics analysis, cell experiments, animal models, and multi-omics approaches to reveal differences in glucose metabolism phenotypes among HNSCC patients and elucidated the underlying molecular mechanisms driving these differences. Our findings showed that NSD1 mutation status affects the glucose metabolism phenotype in HNSCC, with NSD1 wild-type HNSCC exhibiting higher mitochondrial respiration and NSD1 mutant HNSCC showing weaker mitochondrial respiration but enhanced glycolysis. We further demonstrated that NSD1 regulates mitochondrial respiration in HNSCC via epigenetic modulation of the TGFB2/PPARGC1A signaling axis. Additionally, we found that NSD1 wild-type HNSCC is more sensitive to mitochondrial respiration inhibitors, whereas NSD1 mutant HNSCC shows increased sensitivity to glycolysis inhibitors. In summary, we found that NSD1 can epigenetically regulate the TGFB2/PPARGC1A axis to modulate mitochondrial respiration and sensitivity to metabolic inhibitors in HNSCC. These findings suggest a novel strategy for selecting metabolic inhibitors for HNSCC based on the NSD1 gene status of patients. © 2025 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Shouyi Tang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
- Yunnan Key Laboratory of Stomatology, Kunming Medical University, Kunming, PR China
| | - Qing Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Zhen Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Luyao Cai
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Dan Pan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Jing Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Yu Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
| | - Ying-Qiang Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, PR China
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McIntyre TI, Valdez O, Kochhar NP, Davidson B, Samad B, Qiu L, Hu K, Combes AJ, Erlebacher A. KDM6B-dependent epigenetic programming of uterine fibroblasts in early pregnancy regulates parturition timing in mice. Cell 2025; 188:1265-1279.e18. [PMID: 39842437 PMCID: PMC11890963 DOI: 10.1016/j.cell.2024.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 09/03/2024] [Accepted: 12/13/2024] [Indexed: 01/24/2025]
Abstract
Current efforts investigating parturition timing mechanisms have focused on the proximal triggers of labor onset generated in late pregnancy. By studying the delayed parturition phenotype of mice with uterine fibroblast deficiencies in the histone H3K27me3 demethylase KDM6B, we provide evidence that parturition timing is regulated by events that take place in early pregnancy. Immediately after copulation, uterine fibroblasts engage in a locus-specific epigenetic program that abruptly adjusts H3K27me3 levels across their genome. In the absence of KDM6B, many of the adjusted loci over-accumulate H3K27me3. This over-accumulation leads to nearby genes being misexpressed in mid-to-late gestation, a delayed effect partly attributable to a second locus-specific but KDM6B-independent process initiated within uterine fibroblasts soon after implantation. This second process employs progressive H3K27me3 loss to temporally structure post-midgestational patterns of gene induction. Further dissection of the ways uterine programming controls parturition timing may have relevance to human pregnancy complications such as preterm labor.
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Affiliation(s)
- Tara I McIntyre
- Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Omar Valdez
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Nathan P Kochhar
- UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Brittany Davidson
- UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Bushra Samad
- UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Longhui Qiu
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Kenneth Hu
- Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Alexis J Combes
- UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Adrian Erlebacher
- Biomedical Sciences Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Science, School of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
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Ma J, Zhang Y, Li J, Dang Y, Hu D. Regulation of histone H3K27 methylation in inflammation and cancer. MOLECULAR BIOMEDICINE 2025; 6:14. [PMID: 40042761 PMCID: PMC11882493 DOI: 10.1186/s43556-025-00254-x] [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: 08/26/2024] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 03/09/2025] Open
Abstract
Inflammation is a multifaceted defense mechanism of the immune system against infection. Chronic inflammation is intricately linked to all stages of tumorigenesis and is therefore associated with an elevated risk of developing serious cancers. Epigenetic mechanisms have the capacity to trigger inflammation as well as facilitate tumor development and transformation within an inflammatory context. They achieve this by dynamically modulating the expression of both pro-inflammatory and anti-inflammatory cytokines, which in turn sustains chronic inflammation. The aberrant epigenetic landscape reconfigures the transcriptional programs of inflammatory and oncogenic genes. This reconfiguration is pivotal in dictating the biological functions of both tumor cells and immune cells. Aberrant histone H3 lysine 27 site (H3K27) methylation has been shown to be involved in biological behaviors such as inflammation development, tumor progression, and immune response. The establishment and maintenance of this repressive epigenetic mark is dependent on the involvement of the responsible histone modifying enzymes enhancer of zeste homologue 2 (EZH2), jumonji domain containing 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat gene X (UTX) as well as multiple cofactors. In addition, specific pharmacological agents have been shown to modulate H3K27 methylation levels, thereby modulating inflammation and carcinogenesis. This review comprehensively summarises the current characteristics and clinical significance of epigenetic regulation of H3K27 methylation in the context of inflammatory response and tumor progression.
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Affiliation(s)
- Jing Ma
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Yalin Zhang
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Jingyuan Li
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, (Shanghai University of Traditional Chinese Medicine), Shanghai, 200032, China
| | - Yanqi Dang
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, (Shanghai University of Traditional Chinese Medicine), Shanghai, 200032, China.
| | - Dan Hu
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China.
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Wu Q, Yu C, Yu F, Guo Y, Sheng Y, Li L, Li Y, Zhang Y, Hu C, Wang J, He TC, Huang Y, Ni H, Huo Z, Wu W, Wang GG, Lyu J, Qian Z. Evi1 governs Kdm6b-mediated histone demethylation to regulate the Laptm4b-driven mTOR pathway in hematopoietic progenitor cells. J Clin Invest 2024; 134:e173403. [PMID: 39680456 PMCID: PMC11645144 DOI: 10.1172/jci173403] [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: 06/27/2023] [Accepted: 10/24/2024] [Indexed: 12/18/2024] Open
Abstract
Ecotropic viral integration site 1 (EVI1/MECOM) is frequently upregulated in myeloid malignancies. Here, we present an Evi1-transgenic mouse model with inducible expression in hematopoietic stem/progenitor cells (HSPCs). Upon induction of Evi1 expression, mice displayed anemia, thrombocytopenia, lymphopenia, and erythroid and megakaryocyte dysplasia with a significant expansion of committed myeloid progenitor cells, resembling human myelodysplastic syndrome/myeloproliferative neoplasm-like (MDS/MPN-like) disease. Evi1 overexpression prompted HSPCs to exit quiescence and accelerated their proliferation, leading to expansion of committed myeloid progenitors while inhibiting lymphopoiesis. Analysis of global gene expression and Evi1 binding site profiling in HSPCs revealed that Evi1 directly upregulated lysine demethylase 6b (Kdm6b). Subsequently, Kdm6b-mediated H3K27me3 demethylation resulted in activation of various genes, including Laptm4b. Interestingly, KDM6B and LAPTM4B are positively correlated with EVI1 expression in patients with MDS. The EVI1/KDM6B/H3K27me3/LAPTM4B signaling pathway was also identified in EVI1hi human leukemia cell lines. We found that hyperactivation of the LAPTM4B-driven mTOR pathway was crucial for the growth of EVI1hi leukemia cells. Knockdown of Laptm4b partially rescued Evi1-induced abnormal hematopoiesis in vivo. Thus, our study establishes a mouse model to investigate EVI1hi myeloid malignancies, demonstrating the significance of the EVI1-mediated KDM6B/H3K27me3/LAPTM4B signaling axis in their maintenance.
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Affiliation(s)
- Qiong Wu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA
| | - Chunjie Yu
- Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA
| | - Fang Yu
- Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA
| | - Yiran Guo
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
| | - Yue Sheng
- Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA
| | - Liping Li
- Department of Pathology at Geisinger Medical Center, Danville, Pennsylvania, USA
| | - Yafang Li
- Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA
| | - Yutao Zhang
- Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA
- Department of Biostatistics, University of Florida, Gainesville, Florida, USA
| | - Chao Hu
- Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Jue Wang
- Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA
| | - Tong-chuan He
- Department of Orthopaedic Surgery and Rehabilitation Medicine, University of Chicago, Chicago, Illinois, USA
| | - Yong Huang
- Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Hongyu Ni
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Zhiguang Huo
- Department of Biostatistics, University of Florida, Gainesville, Florida, USA
| | - Wenshu Wu
- Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Gang Greg Wang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
| | - Jianxin Lyu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Laboratory Medicine, Zhejiang Provincial People’s Hospital, Affiliate People’s Hospital of Hangzhou Medical College, and
- Laboratory Medicine of Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zhijian Qian
- Department of Medicine and Department of Biochemistry and Molecular Biology, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA
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Louis E, Fu L, Shi YB, Sachs LM. Functions and Mechanism of Thyroid Hormone Receptor Action During Amphibian Development. Endocrinology 2024; 165:bqae137. [PMID: 39397558 PMCID: PMC11497603 DOI: 10.1210/endocr/bqae137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 09/30/2024] [Accepted: 10/10/2024] [Indexed: 10/15/2024]
Abstract
Thyroid hormones and their receptors (TRs) play critical roles during vertebrate development. One of the most dramatic developmental processes regulated by thyroid hormones is frog metamorphosis, which mimics the postembryonic (perinatal) period in mammals. Here, we review some of the findings on the developmental functions of thyroid hormones and TRs as well as their associated mechanisms of action obtained from this model system. More than 2 decades ago, a dual function model was proposed for TR in anuran development. During larval development, unliganded receptors recruit corepressors to repress thyroid hormone response genes to prevent premature metamorphic changes. Subsequently, when thyroid hormone levels rise, liganded receptors recruit coactivators to activate thyroid hormone response genes, leading to metamorphic changes. Over the years, molecular and genetic approaches have provided strong support for this model and have shown that it is applicable to mammalian development as well as to understanding the diverse effects of thyroid hormones in normal physiology and diseases caused by thyroid hormone signaling dysfunction.
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Affiliation(s)
- Emeric Louis
- Unité Mixte de Recherche 7221, Département Adaptation du Vivant, Centre National de la Recherche Scientifique, Muséum National d’Histoire Naturelle, Alliance Sorbonne Universités, 75231 Paris, France
- Section on Molecular Morphogenesis, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Liezhen Fu
- Section on Molecular Morphogenesis, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Yun-Bo Shi
- Section on Molecular Morphogenesis, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Laurent M Sachs
- Unité Mixte de Recherche 7221, Département Adaptation du Vivant, Centre National de la Recherche Scientifique, Muséum National d’Histoire Naturelle, Alliance Sorbonne Universités, 75231 Paris, France
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Peeters JGC, Silveria S, Ozdemir M, Ramachandran S, DuPage M. Hyperactivating EZH2 to augment H3K27me3 levels in regulatory T cells enhances immune suppression by driving early effector differentiation. Cell Rep 2024; 43:114724. [PMID: 39264807 PMCID: PMC12052300 DOI: 10.1016/j.celrep.2024.114724] [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: 03/21/2024] [Revised: 07/17/2024] [Accepted: 08/21/2024] [Indexed: 09/14/2024] Open
Abstract
The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and Ezh2 deletion in Treg cells causes autoimmunity. Here, we assess whether increasing H3K27me3 levels, by using an Ezh2Y641F gain-of-function mutation, will improve Treg cell function. We find that Treg cells expressing Ezh2Y641F display an effector Treg phenotype, are poised for improved homing to organ tissues, and can accelerate remission from autoimmunity. The H3K27me3 landscape and transcriptome of naive Ezh2Y641F Treg cells exhibit a redistribution of H3K27me3 modifications that recapitulates the gene expression profile of activated Ezh2WT Treg cells after CD28 co-stimulation. Altogether, increased H3K27me3 levels promote the differentiation of effector Treg cells that can better suppress autoimmunity.
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Affiliation(s)
- Janneke G C Peeters
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Stephanie Silveria
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Merve Ozdemir
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Srinivas Ramachandran
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA; RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO 80045, USA.
| | - Michel DuPage
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
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Li X, Chen RY, Shi JJ, Li CY, Liu YJ, Gao C, Gao MR, Zhang S, Lu JF, Cao JF, Yang GJ, Chen J. Emerging role of Jumonji domain-containing protein D3 in inflammatory diseases. J Pharm Anal 2024; 14:100978. [PMID: 39315124 PMCID: PMC11417268 DOI: 10.1016/j.jpha.2024.100978] [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: 12/18/2023] [Revised: 04/10/2024] [Accepted: 04/15/2024] [Indexed: 09/25/2024] Open
Abstract
Jumonji domain-containing protein D3 (JMJD3) is a 2-oxoglutarate-dependent dioxygenase that specifically removes transcriptional repression marks di- and tri-methylated groups from lysine 27 on histone 3 (H3K27me2/3). The erasure of these marks leads to the activation of some associated genes, thereby influencing various biological processes, such as development, differentiation, and immune response. However, comprehensive descriptions regarding the relationship between JMJD3 and inflammation are lacking. Here, we provide a comprehensive overview of JMJD3, including its structure, functions, and involvement in inflammatory pathways. In addition, we summarize the evidence supporting JMJD3's role in several inflammatory diseases, as well as the potential therapeutic applications of JMJD3 inhibitors. Additionally, we also discuss the challenges and opportunities associated with investigating the functions of JMJD3 and developing targeted inhibitors and propose feasible solutions to provide valuable insights into the functional exploration and discovery of potential drugs targeting JMJD3 for inflammatory diseases.
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Affiliation(s)
- Xiang Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Ru-Yi Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Jin-Jin Shi
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Chang-Yun Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Yan-Jun Liu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Chang Gao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Ming-Rong Gao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Shun Zhang
- Ningbo No. 2 Hospital, Ningbo, Zhejiang, 315211, China
- China Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, Zhejiang, 315211, China
| | - Jian-Fei Lu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Jia-Feng Cao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Guan-Jun Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Jiong Chen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315211, China
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Pottmeier P, Nikolantonaki D, Lanner F, Peuckert C, Jazin E. Sex-biased gene expression during neural differentiation of human embryonic stem cells. Front Cell Dev Biol 2024; 12:1341373. [PMID: 38764741 PMCID: PMC11101176 DOI: 10.3389/fcell.2024.1341373] [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: 11/20/2023] [Accepted: 04/16/2024] [Indexed: 05/21/2024] Open
Abstract
Sex differences in the developing human brain are primarily attributed to hormonal influence. Recently however, genetic differences and their impact on the developing nervous system have attracted increased attention. To understand genetically driven sexual dimorphisms in neurodevelopment, we investigated genome-wide gene expression in an in vitro differentiation model of male and female human embryonic stem cell lines (hESC), independent of the effects of human sex hormones. Four male and four female-derived hESC lines were differentiated into a population of mixed neurons over 37 days. Differential gene expression and gene set enrichment analyses were conducted on bulk RNA sequencing data. While similar differentiation tendencies in all cell lines demonstrated the robustness and reproducibility of our differentiation protocol, we found sex-biased gene expression already in undifferentiated ESCs at day 0, but most profoundly after 37 days of differentiation. Male and female cell lines exhibited sex-biased expression of genes involved in neurodevelopment, suggesting that sex influences the differentiation trajectory. Interestingly, the highest contribution to sex differences was found to arise from the male transcriptome, involving both Y chromosome and autosomal genes. We propose 13 sex-biased candidate genes (10 upregulated in male cell lines and 3 in female lines) that are likely to affect neuronal development. Additionally, we confirmed gene dosage compensation of X/Y homologs escaping X chromosome inactivation through their Y homologs and identified a significant overexpression of the Y-linked demethylase UTY and KDM5D in male hESC during neuron development, confirming previous results in neural stem cells. Our results suggest that genetic sex differences affect neuronal differentiation trajectories, which could ultimately contribute to sex biases during human brain development.
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Affiliation(s)
- Philipp Pottmeier
- Department of Organismal Biology, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden
| | - Danai Nikolantonaki
- Department of Organismal Biology, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden
| | - Fredrik Lanner
- Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
| | - Christiane Peuckert
- Department of Organismal Biology, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden
- The Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Elena Jazin
- Department of Organismal Biology, Evolutionary Biology Centre, Uppsala University, Uppsala, Sweden
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10
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Peeters JGC, Silveria S, Ozdemir M, Ramachandran S, DuPage M. Increased EZH2 function in regulatory T cells promotes their capacity to suppress autoimmunity by driving effector differentiation prior to activation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.05.588284. [PMID: 38645261 PMCID: PMC11030251 DOI: 10.1101/2024.04.05.588284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2024]
Abstract
The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and Ezh2 deletion in Treg cells causes autoimmunity. Here we assessed whether increased EZH2 activity in Treg cells would improve Treg cell function. Using an Ezh2 gain-of-function mutation, Ezh2 Y641F , we found that Treg cells expressing Ezh2 Y641F displayed an increased effector Treg phenotype and were poised for improved homing to organ tissues. Expression of Ezh2 Y641F in Treg cells led to more rapid remission from autoimmunity. H3K27me3 profiling and transcriptomic analysis revealed a redistribution of H3K27me3, which prompted a gene expression profile in naïve Ezh2 Y641F Treg cells that recapitulated aspects of CD28-activated Ezh2 WT Treg cells. Altogether, increased EZH2 activity promotes the differentiation of effector Treg cells that can better suppress autoimmunity. Highlights EZH2 function promotes effector differentiation of Treg cells.EZH2 function promotes Treg cell migration to organ tissues.EZH2 function in Treg cells improves remission from autoimmunity.EZH2 function poises naïve Treg cells to adopt a CD28-activated phenotype.
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11
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Chen D, Cai B, Zhu Y, Ma Y, Yu X, Xiong J, Shen J, Tie W, Zhang Y, Guo F. Targeting histone demethylases JMJD3 and UTX: selenium as a potential therapeutic agent for cervical cancer. Clin Epigenetics 2024; 16:51. [PMID: 38576048 PMCID: PMC10993516 DOI: 10.1186/s13148-024-01665-3] [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: 12/09/2023] [Accepted: 03/26/2024] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND The intriguing connection between selenium and cancer resembles a captivating puzzle that keeps researchers engaged and curious. While selenium has shown promise in reducing cancer risks through supplementation, its interaction with epigenetics in cervical cancer remains a fascinating yet largely unexplored realm. Unraveling the intricacies of selenium's role and its interaction with epigenetic factors could unlock valuable insights in the battle against this complex disease. RESULT Selenium has shown remarkable inhibitory effects on cervical cancer cells in various ways. In in vitro studies, it effectively inhibits the proliferation, migration, and invasion of cervical cancer cells, while promoting apoptosis. Selenium also demonstrates significant inhibitory effects on human cervical cancer-derived organoids. Furthermore, in an in vivo study, the administration of selenium dioxide solution effectively suppresses the growth of cervical cancer tumors in mice. One of the mechanisms behind selenium's inhibitory effects is its ability to inhibit histone demethylases, specifically JMJD3 and UTX. This inhibition is observed both in vitro and in vivo. Notably, when JMJD3 and UTX are inhibited with GSK-J4, similar biological effects are observed in both in vitro and in vivo models, effectively inhibiting organoid models derived from cervical cancer patients. Inhibiting JMJD3 and UTX also induces G2/M phase arrest, promotes cellular apoptosis, and reverses epithelial-mesenchymal transition (EMT). ChIP-qPCR analysis confirms that JMJD3 and UTX inhibition increases the recruitment of a specific histone modification, H3K27me3, to the transcription start sites (TSS) of target genes in cervical cancer cells (HeLa and SiHa cells). Furthermore, the expressions of JMJD3 and UTX are found to be significantly higher in cervical cancer tissues compared to adjacent normal cervical tissues, suggesting their potential as therapeutic targets. CONCLUSIONS Our study highlights the significant inhibitory effects of selenium on the growth, migration, and invasion of cervical cancer cells, promoting apoptosis and displaying promising potential as a therapeutic agent. We identified the histone demethylases JMJD3 and UTX as specific targets of selenium, and their inhibition replicates the observed effects on cancer cell behavior. These findings suggest that JMJD3 and UTX could be valuable targets for selenium-based treatments of cervical cancer.
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Affiliation(s)
- Dezhi Chen
- Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315100, Zhejiang Province, China
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Bo Cai
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, China
- Jiangxi Maternal and Child Health Hospital, Nanchang, 330008, Jiangxi Province, China
| | - Yingying Zhu
- Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315100, Zhejiang Province, China
| | - Yimin Ma
- Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315100, Zhejiang Province, China
| | - Xiaoting Yu
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Jieqi Xiong
- Jiangxi Maternal and Child Health Hospital, Nanchang, 330008, Jiangxi Province, China
| | - Jiaying Shen
- Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315100, Zhejiang Province, China
| | - Weiwei Tie
- Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315100, Zhejiang Province, China
| | - Yisheng Zhang
- Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315100, Zhejiang Province, China
| | - Fei Guo
- Ningbo Institute of Innovation for Combined Medicine and Engineering (NIIME), Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, 315100, Zhejiang Province, China.
- The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, China.
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12
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Chen H, Yu S, Ma R, Deng L, Yi Y, Niu M, Xu C, Xiao ZXJ. Hypoxia-activated XBP1s recruits HDAC2-EZH2 to engage epigenetic suppression of ΔNp63α expression and promote breast cancer metastasis independent of HIF1α. Cell Death Differ 2024; 31:447-459. [PMID: 38413797 PMCID: PMC11043437 DOI: 10.1038/s41418-024-01271-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 02/29/2024] Open
Abstract
Hypoxia is a hallmark of cancer development. However, the molecular mechanisms by which hypoxia promotes tumor metastasis are not fully understood. In this study, we demonstrate that hypoxia promotes breast cancer metastasis through suppression of ΔNp63α in a HIF1α-independent manner. We show that hypoxia-activated XBP1s forms a stable repressor protein complex with HDAC2 and EZH2 to suppress ΔNp63α transcription. Notably, H3K27ac is predominantly occupied on the ΔNp63 promoter under normoxia, while H3K27me3 on the promoter under hypoxia. We show that XBP1s binds to the ΔNp63 promoter to recruit HDAC2 and EZH2 in facilitating the switch of H3K27ac to H3K27me3. Pharmacological inhibition or the knockdown of either HDAC2 or EZH2 leads to increased H3K27ac, accompanied by the reduced H3K27me3 and restoration of ΔNp63α expression suppressed by hypoxia, resulting in inhibition of cell migration. Furthermore, the pharmacological inhibition of IRE1α, but not HIF1α, upregulates ΔNp63α expression in vitro and inhibits tumor metastasis in vivo. Clinical analyses reveal that reduced p63 expression is correlated with the elevated expression of XBP1, HDAC2, or EZH2, and is associated with poor overall survival in human breast cancer patients. Together, these results indicate that hypoxia-activated XBP1s modulates the epigenetic program in suppression of ΔNp63α to promote breast cancer metastasis independent of HIF1α and provides a molecular basis for targeting the XBP1s/HDAC2/EZH2-ΔNp63α axis as a putative strategy in the treatment of breast cancer metastasis.
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Affiliation(s)
- Hu Chen
- School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, China.
| | - Shuhan Yu
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Ruidong Ma
- School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, China
| | - Liyuan Deng
- School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, China
| | - Yong Yi
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Mengmeng Niu
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Chuan Xu
- Department of Oncology & Cancer Institute, Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
| | - Zhi-Xiong Jim Xiao
- Department of Oncology & Cancer Institute, Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
- Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China.
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
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13
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Kim H, Lebeau B, Papadopoli D, Jovanovic P, Russo M, Avizonis D, Morita M, Afzali F, Ursini-Siegel J, Postovit LM, Witcher M, Topisirovic I. MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors. iScience 2024; 27:109188. [PMID: 38433910 PMCID: PMC10904987 DOI: 10.1016/j.isci.2024.109188] [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: 11/08/2023] [Revised: 01/11/2024] [Accepted: 02/06/2024] [Indexed: 03/05/2024] Open
Abstract
Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR), which is a pivotal metabolic regulator, and epigenetic modifications remains poorly understood. Our results show that mTORC1 activation caused by the abrogation of its negative regulator tuberous sclerosis complex 2 (TSC2) coincides with increased levels of the histone modification H3K27me3 but not H3K4me3 or H3K9me3. This selective H3K27me3 induction was mediated via 4E-BP-dependent increase in EZH2 protein levels. Surprisingly, mTOR inhibition also selectively induced H3K27me3. This was independent of TSC2, and was paralleled by reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the induction of H3K27me3 may potentiate the anti-proliferative effects of mTOR inhibitors.
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Affiliation(s)
- HaEun Kim
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
| | - Benjamin Lebeau
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - David Papadopoli
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada
| | - Predrag Jovanovic
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
| | - Mariana Russo
- Goodman Cancer Research Centre, Montréal, QC H3A 1A3, Canada
| | - Daina Avizonis
- Goodman Cancer Research Centre, Montréal, QC H3A 1A3, Canada
| | - Masahiro Morita
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Farzaneh Afzali
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada
| | - Josie Ursini-Siegel
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada
- Department of Biochemistry, McGill University, Montreal, QC H3A 0G4, Canada
| | - Lynne-Marie Postovit
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada
| | - Michael Witcher
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada
| | - Ivan Topisirovic
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada
- Department of Biochemistry, McGill University, Montreal, QC H3A 0G4, Canada
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14
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Ge G, Zhang P, Sui P, Chen S, Yang H, Guo Y, Rubalcava IP, Noor A, Delma CR, Agosto-Peña J, Geng H, Medina EA, Liang Y, Nimer SD, Mesa R, Abdel-Wahab O, Xu M, Yang FC. Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models. J Clin Invest 2024; 134:e163964. [PMID: 37917239 PMCID: PMC10760961 DOI: 10.1172/jci163964] [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: 11/14/2022] [Accepted: 10/31/2023] [Indexed: 11/04/2023] Open
Abstract
ASXL1 mutation frequently occurs in all forms of myeloid malignancies and is associated with aggressive disease and poor prognosis. ASXL1 recruits Polycomb repressive complex 2 (PRC2) to specific gene loci to repress transcription through trimethylation of histone H3 on lysine 27 (H3K27me3). ASXL1 alterations reduce H3K27me3 levels, which results in leukemogenic gene expression and the development of myeloid malignancies. Standard therapies for myeloid malignancies have limited efficacy when mutated ASXL1 is present. We discovered upregulation of lysine demethylase 6B (KDM6B), a demethylase for H3K27me3, in ASXL1-mutant leukemic cells, which further reduces H3K27me3 levels and facilitates myeloid transformation. Here, we demonstrated that heterozygous deletion of Kdm6b restored H3K27me3 levels and normalized dysregulated gene expression in Asxl1Y588XTg hematopoietic stem/progenitor cells (HSPCs). Furthermore, heterozygous deletion of Kdm6b decreased the HSPC pool, restored their self-renewal capacity, prevented biased myeloid differentiation, and abrogated progression to myeloid malignancies in Asxl1Y588XTg mice. Importantly, administration of GSK-J4, a KDM6B inhibitor, not only restored H3K27me3 levels but also reduced the disease burden in NSG mice xenografted with human ASXL1-mutant leukemic cells in vivo. This preclinical finding provides compelling evidence that targeting KDM6B may be a therapeutic strategy for myeloid malignancies with ASXL1 mutations.
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Affiliation(s)
- Guo Ge
- Department of Cell Systems and Anatomy
| | - Peng Zhang
- Department of Cell Systems and Anatomy
- Mays Cancer Center
| | - Pinpin Sui
- Department of Cell Systems and Anatomy
- Mays Cancer Center
| | - Shi Chen
- Department of Molecular Medicine, and
| | - Hui Yang
- Department of Cell Systems and Anatomy
| | - Ying Guo
- Department of Cell Systems and Anatomy
| | | | - Asra Noor
- Department of Cell Systems and Anatomy
| | - Caroline R. Delma
- Department of Cell Systems and Anatomy
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | | | - Hui Geng
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Edward A. Medina
- Mays Cancer Center
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Ying Liang
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA
| | - Stephen D. Nimer
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | | | - Omar Abdel-Wahab
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Mingjiang Xu
- Mays Cancer Center
- Department of Molecular Medicine, and
| | - Feng-Chun Yang
- Department of Cell Systems and Anatomy
- Mays Cancer Center
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15
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Qiao Y, Li L, Bai L, Gao Y, Yang Y, Wang L, Wang X, Liang Z, Xu J. Upregulation of lysine-specific demethylase 6B aggravates inflammatory pain through H3K27me3 demethylation-dependent production of TNF-α in the dorsal root ganglia and spinal dorsal horn in rats. CNS Neurosci Ther 2023; 29:3479-3492. [PMID: 37287407 PMCID: PMC10580362 DOI: 10.1111/cns.14281] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 05/03/2023] [Accepted: 05/09/2023] [Indexed: 06/09/2023] Open
Abstract
AIMS Lysine-specific demethylase 6B (KDM6B) serves as a key mediator of gene transcription. It regulates expression of proinflammatory cytokines and chemokines in variety of diseases. Herein, the role and the underlying mechanisms of KDM6B in inflammatory pain were studied. METHODS The inflammatory pain was conducted by intraplantar injection of complete Freund's adjuvant (CFA) in rats. Immunofluorescence, Western blotting, qRT-PCR, and chromatin immunoprecipitation (ChIP)-PCR were performed to investigate the underlying mechanisms. RESULTS CFA injection led to upregulation of KDM6B and decrease in the level of H3K27me3 in the dorsal root ganglia (DRG) and spinal dorsal horn. The mechanical allodynia and thermal hyperalgesia following CFA were alleviated by the treatment of intrathecal injection of GSK-J4, and by microinjection of AAV-EGFP-KDM6B shRNA in the sciatic nerve or in lumbar 5 dorsal horn. The increased production of tumor necrosis factor-α (TNF-α) following CFA in the DRGs and dorsal horn was inhibited by these treatments. ChIP-PCR showed that CFA-induced increased binding of nuclear factor κB with TNF-α promoter was repressed by the treatment of microinjection of AAV-EGFP-KDM6B shRNA. CONCLUSIONS These results suggest that upregulated KDM6B via facilitating TNF-α expression in the DRG and spinal dorsal horn aggravates inflammatory pain.
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Affiliation(s)
- Yiming Qiao
- Department of Physiology and Neurobiology, School of Basic Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Liren Li
- Department of Physiology and Neurobiology, School of Basic Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Liying Bai
- Department of Physiology and Neurobiology, School of Basic Medical SciencesZhengzhou UniversityZhengzhouChina
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated HospitalZhengzhou UniversityZhengzhouChina
| | - Yan Gao
- Department of Physiology and Neurobiology, School of Basic Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Yin Yang
- Department of Physiology and Neurobiology, School of Basic Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Li Wang
- Department of Physiology and Neurobiology, School of Basic Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Xueli Wang
- Department of Physiology and Neurobiology, School of Basic Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Zongyi Liang
- Department of Physiology and Neurobiology, School of Basic Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Ji‐Tian Xu
- Department of Physiology and Neurobiology, School of Basic Medical SciencesZhengzhou UniversityZhengzhouChina
- Neuroscience Research InstituteZhengzhou UniversityZhengzhouChina
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16
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Ngubo M, Moradi F, Ito CY, Stanford WL. Tissue-Specific Tumour Suppressor and Oncogenic Activities of the Polycomb-like Protein MTF2. Genes (Basel) 2023; 14:1879. [PMID: 37895228 PMCID: PMC10606531 DOI: 10.3390/genes14101879] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 09/22/2023] [Accepted: 09/23/2023] [Indexed: 10/29/2023] Open
Abstract
The Polycomb repressive complex 2 (PRC2) is a conserved chromatin-remodelling complex that catalyses the trimethylation of histone H3 lysine 27 (H3K27me3), a mark associated with gene silencing. PRC2 regulates chromatin structure and gene expression during organismal and tissue development and tissue homeostasis in the adult. PRC2 core subunits are associated with various accessory proteins that modulate its function and recruitment to target genes. The multimeric composition of accessory proteins results in two distinct variant complexes of PRC2, PRC2.1 and PRC2.2. Metal response element-binding transcription factor 2 (MTF2) is one of the Polycomb-like proteins (PCLs) that forms the PRC2.1 complex. MTF2 is highly conserved, and as an accessory subunit of PRC2, it has important roles in embryonic stem cell self-renewal and differentiation, development, and cancer progression. Here, we review the impact of MTF2 in PRC2 complex assembly, catalytic activity, and spatiotemporal function. The emerging paradoxical evidence suggesting that MTF2 has divergent roles as either a tumour suppressor or an oncogene in different tissues merits further investigations. Altogether, our review illuminates the context-dependent roles of MTF2 in Polycomb group (PcG) protein-mediated epigenetic regulation. Its impact on disease paves the way for a deeper understanding of epigenetic regulation and novel therapeutic strategies.
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Affiliation(s)
- Mzwanele Ngubo
- The Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON K1H 8M5, Canada
| | - Fereshteh Moradi
- The Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Caryn Y. Ito
- The Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - William L. Stanford
- The Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON K1H 8M5, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
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17
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Alharthi J, Pan Z, Gloss BS, McLeod D, Weltman M, George J, Eslam M. Loss of metabolic adaptation in lean MAFLD is driven by endotoxemia leading to epigenetic reprogramming. Metabolism 2023; 144:155583. [PMID: 37146900 DOI: 10.1016/j.metabol.2023.155583] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 04/24/2023] [Accepted: 04/28/2023] [Indexed: 05/07/2023]
Abstract
Lean patients with MAFLD have an initial adaptive metabolic response characterised by increased serum bile acids and Farnesoid X Receptor (FXR) activity. How this adaptive response wanes resulting in an equal or perhaps worse long-term adverse outcome compared to patients with obese MAFLD is not known. We show that patients with lean MAFLD have endotoxemia while their macrophages demonstrate excess production of inflammatory cytokines in response to activation by Toll-like receptor (TLR) ligands when compared to healthy subjects. Alterations of the lean MAFLD macrophage epigenome drives this response and suppresses bile acids signalling to drive inflammation. Our data suggests that selectively restoring bile acids signalling might restore adaptive metabolic responses in patients with MAFLD who are lean.
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Affiliation(s)
- Jawaher Alharthi
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia; Department of Biotechnology, Faculty of Science, Taif University, Taif, Saudi Arabia
| | - Ziyan Pan
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia
| | - Brian S Gloss
- Westmead Research Hub, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Duncan McLeod
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, Australia
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
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18
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Li Y, Hu M, Xie J, Li S, Dai L. Dysregulation of histone modifications in bone marrow mesenchymal stem cells during skeletal ageing: roles and therapeutic prospects. Stem Cell Res Ther 2023; 14:166. [PMID: 37357311 DOI: 10.1186/s13287-023-03393-6] [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: 10/16/2022] [Accepted: 05/31/2023] [Indexed: 06/27/2023] Open
Abstract
Age-associated bone diseases such as osteoporosis (OP) are common in the elderly due to skeletal ageing. The process of skeletal ageing can be accelerated by reduced proliferation and osteogenesis of bone marrow mesenchymal stem cells (BM-MSCs). Senescence of BM-MSCs is a main driver of age-associated bone diseases, and the fate of BM-MSCs is tightly regulated by histone modifications, such as methylation and acetylation. Dysregulation of histone modifications in BM-MSCs may activate the genes related to the pathogenesis of skeletal ageing and age-associated bone diseases. Here we summarize the histone methylation and acetylation marks and their regulatory enzymes that affect BM-MSC self-renewal, differentiation and senescence. This review not only describes the critical roles of histone marks in modulating BM-MSC functions, but also underlines the potential of epigenetic enzymes as targets for treating age-associated bone diseases. In the future, more effective therapeutic approaches based on these epigenetic targets will be developed and will benefit elderly individuals with bone diseases, such as OP.
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Affiliation(s)
- Yujue Li
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Mingxing Hu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jinwei Xie
- Department of Orthopedics Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Shuangqing Li
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Lunzhi Dai
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Ramesh V, Liu F, Minto MS, Chan U, West AE. Bidirectional regulation of postmitotic H3K27me3 distributions underlie cerebellar granule neuron maturation dynamics. eLife 2023; 12:e86273. [PMID: 37092728 PMCID: PMC10181825 DOI: 10.7554/elife.86273] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/21/2023] [Indexed: 04/25/2023] Open
Abstract
The functional maturation of neurons is a prolonged process that extends past the mitotic exit and is mediated by the chromatin-dependent orchestration of gene transcription programs. We find that expression of this maturation gene program in mouse cerebellar granule neurons (CGNs) requires dynamic changes in the genomic distribution of histone H3 lysine 27 trimethylation (H3K27me3), demonstrating a function for this chromatin modification beyond its role in cell fate specification. The developmental loss of H3K27me3 at promoters of genes activated as CGNs mature is facilitated by the lysine demethylase and ASD-risk gene, Kdm6b. Interestingly, inhibition of the H3K27 methyltransferase EZH2 in newborn CGNs not only blocks the repression of progenitor genes but also impairs the induction of mature CGN genes, showing the importance of bidirectional H3K27me3 regulation across the genome. These data demonstrate that H3K27me3 turnover in developing postmitotic neurons regulates the temporal coordination of gene expression programs that underlie functional neuronal maturation.
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Affiliation(s)
- Vijyendra Ramesh
- Molecular Cancer Biology Program, Duke UniversityDurhamUnited States
| | - Fang Liu
- Department of Neurobiology, Duke UniversityDurhamUnited States
| | - Melyssa S Minto
- Department of Neurobiology, Duke UniversityDurhamUnited States
| | - Urann Chan
- Department of Neurobiology, Duke UniversityDurhamUnited States
| | - Anne E West
- Molecular Cancer Biology Program, Duke UniversityDurhamUnited States
- Department of Neurobiology, Duke UniversityDurhamUnited States
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20
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Hasebe T, Fujimoto K, Ishizuya-Oka A. Stem cell development involves divergent thyroid hormone receptor subtype expression and epigenetic modifications in the amphibian intestine during metamorphosis. VITAMINS AND HORMONES 2023; 122:1-22. [PMID: 36863790 DOI: 10.1016/bs.vh.2022.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In the amphibian intestine during metamorphosis, most of the larval epithelial cells undergo apoptosis, while a small number of the epithelial cells dedifferentiate into stem cells (SCs). The SCs actively proliferate and then newly generate the adult epithelium analogous to the mammalian counterpart, which is continuously renewed from the SCs throughout adulthood. This larval-to-adult intestinal remodeling can be experimentally induced by thyroid hormone (TH) through interacting with the surrounding connective tissue that develops as the stem cell niche. Thus, the amphibian intestine provides us a valuable opportunity to study how the SCs and their niche are formed during development. To clarify the TH-induced and evolutionally conserved mechanism of SC development at the molecular level, numerous TH response genes have been identified in the Xenopus laevis intestine over the last three decades and extensively analyzed for their expression and function by using wild-type and transgenic Xenopus tadpoles. Interestingly, accumulating evidence indicates that thyroid hormone receptor (TR) epigenetically regulates the expression of TH response genes involved in the remodeling. In this review, we highlight recent progress in the understanding of SC development, focusing on epigenetic gene regulation by TH/TR signaling in the X. laevis intestine. We here propose that two subtypes of TRs, TRα and TRβ, play distinct roles in the intestinal SC development via different histone modifications in different cell types.
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Affiliation(s)
- Takashi Hasebe
- Department of Biology, Nippon Medical School, Tokyo, Japan.
| | - Kenta Fujimoto
- Department of Biology, Nippon Medical School, Tokyo, Japan
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21
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KDM6B promotes gastric carcinogenesis and metastasis via upregulation of CXCR4 expression. Cell Death Dis 2022; 13:1068. [PMID: 36564369 PMCID: PMC9789124 DOI: 10.1038/s41419-022-05458-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 12/24/2022]
Abstract
KDM6B (Lysine-specific demethylase 6B) is a histone lysine demethyltransferase that plays a key role in many types of cancers. However, its potential role in gastric cancer (GC) remains unclear. Here, we focused on the clinical significance and potential role of KDM6B in GC. We found that the KDM6B expression is upregulated in GC tissues and that its high expression in patients is related to poor prognosis. KDM6B ectopic expression promotes GC cells' proliferation and metastasis, while its inhibition has opposite effects in vitro and in vivo. Mechanistically, KDM6B promotes GC cells proliferation and metastasis through its enzymatic activity through the induction of H3K27me3 demethylation near the CXCR4 (C-X-C chemokine receptor type 4) promoter region, resulting in the upregulation of CXCR4 expression. Furthermore, H. pylori was found to induce KDM6B expression. In conclusion, our results suggest that KDM6B is aberrantly expressed in GC and plays a key role in gastric carcinogenesis and metastasis through CXCR4 upregulation. Our work also suggests that KDM6B may be a potential oncogenic factor and a therapeutic target for GC.
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22
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Kolev HM, Swisa A, Manduchi E, Lan Y, Stine RR, Testa G, Kaestner KH. H3K27me3 Demethylases Maintain the Transcriptional and Epigenomic Landscape of the Intestinal Epithelium. Cell Mol Gastroenterol Hepatol 2022; 15:821-839. [PMID: 36503150 PMCID: PMC9971508 DOI: 10.1016/j.jcmgh.2022.12.001] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 11/30/2022] [Accepted: 12/01/2022] [Indexed: 02/23/2023]
Abstract
BACKGROUND & AIMS Although trimethylation of histone H3 lysine 27 (H3K27me3) by polycomb repressive complex 2 is required for intestinal function, the role of the antagonistic process-H3K27me3 demethylation-in the intestine remains unknown. The aim of this study was to determine the contribution of H3K27me3 demethylases to intestinal homeostasis. METHODS An inducible mouse model was used to simultaneously ablate the 2 known H3K27me3 demethylases, lysine (K)-specific demethylase 6A (Kdm6a) and lysine (K)-specific demethylase 6B (Kdm6b), from the intestinal epithelium. Mice were analyzed at acute and prolonged time points after Kdm6a/b ablation. Cellular proliferation and differentiation were measured using immunohistochemistry, while RNA sequencing and chromatin immunoprecipitation followed by sequencing for H3K27me3 were used to identify gene expression and chromatin changes after Kdm6a/b loss. Intestinal epithelial renewal was evaluated using a radiation-induced injury model, while Paneth cell homeostasis was measured via immunohistochemistry, immunoblot, and transmission electron microscopy. RESULTS We did not detect any effect of Kdm6a/b ablation on intestinal cell proliferation or differentiation toward the secretory cell lineages. Acute and prolonged Kdm6a/b loss perturbed expression of gene signatures belonging to multiple cell lineages (adjusted P value < .05), and a set of 72 genes was identified as being down-regulated with an associated increase in H3K27me3 levels after Kdm6a/b ablation (false discovery rate, <0.05). After prolonged Kdm6a/b loss, dysregulation of the Paneth cell gene signature was associated with perturbed matrix metallopeptidase 7 localization (P < .0001) and expression. CONCLUSIONS Although KDM6A/B does not regulate intestinal cell differentiation, both enzymes are required to support the full transcriptomic and epigenomic landscape of the intestinal epithelium and the expression of key Paneth cell genes.
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Affiliation(s)
- Hannah M Kolev
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Avital Swisa
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Elisabetta Manduchi
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Yemin Lan
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Rachel R Stine
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Giuseppe Testa
- Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Klaus H Kaestner
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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23
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Alharthi J, Bayoumi A, Thabet K, Pan Z, Gloss BS, Latchoumanin O, Lundberg M, Twine NA, McLeod D, Alenizi S, Adams LA, Weltman M, Berg T, Liddle C, George J, Eslam M. A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes. Nat Commun 2022; 13:7430. [PMID: 36473860 PMCID: PMC9726889 DOI: 10.1038/s41467-022-35158-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
The breakdown of toll-like receptor (TLR) tolerance results in tissue damage, and hyperactivation of the TLRs and subsequent inflammatory consequences have been implicated as risk factors for more severe forms of disease and poor outcomes from various diseases including COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a negative regulator of TLR signalling. MBOAT7 deficiency in macrophages as observed in patients with MAFLD and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can potentially be explored as a therapeutic target for diseases associated with dysregulation of the TLR signalling cascade.
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Affiliation(s)
- Jawaher Alharthi
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
- Department of Biotechnology, Faculty of Science, Taif University, Taif, Saudi Arabia
| | - Ali Bayoumi
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Khaled Thabet
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, 6111, Egypt
| | - Ziyan Pan
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Brian S Gloss
- Westmead Research Hub, Westmead Institute for Medical Research, Sydney, NSW, Australia
| | - Olivier Latchoumanin
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Mischa Lundberg
- Transformational Bioinformatics, Commonwealth Scientific and Industrial Research Organisation, Sydney, NSW, Australia
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia
- The University of Queensland Faculty of Medicine, Brisbane, QLD, Australia
| | - Natalie A Twine
- Transformational Bioinformatics, Commonwealth Scientific and Industrial Research Organisation, Sydney, NSW, Australia
| | - Duncan McLeod
- Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, NSW, Australia
| | - Shafi Alenizi
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Leon A Adams
- Medical School, Sir Charles Gairdner Hospital Unit, University of Western Australia, Nedlands, WA, Australia
| | - Martin Weltman
- Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Christopher Liddle
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.
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24
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Farooq U, Notani D. Transcriptional regulation of INK4/ARF locus by cis and trans mechanisms. Front Cell Dev Biol 2022; 10:948351. [PMID: 36158211 PMCID: PMC9500187 DOI: 10.3389/fcell.2022.948351] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/09/2022] [Indexed: 12/12/2022] Open
Abstract
9p21 locus is one of the most reproducible regions in genome-wide association studies (GWAS). The region harbors CDKN2A/B genes that code for p16INK4a, p15INK4b, and p14ARF proteins, and it also harbors a long gene desert adjacent to these genes. The polymorphisms that are associated with several diseases and cancers are present in these genes and the gene desert region. These proteins are critical cell cycle regulators whose transcriptional dysregulation is strongly linked with cellular regeneration, stemness, aging, and cancers. Given the importance of this locus, intense scientific efforts on understanding the regulation of these genes via promoter-driven mechanisms and recently, via the distal regulatory mechanism have provided major insights. In this review, we describe these mechanisms and propose the ways by which this locus can be targeted in pathologies and aging.
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Affiliation(s)
- Umer Farooq
- Genetics and Development, National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore, India
- The University of Trans-Disciplinary Health Sciences and Technology, Bangalore, India
| | - Dimple Notani
- Genetics and Development, National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore, India
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25
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Liang H, Liu B, Gao Y, Nie J, Feng S, Yu W, Wen S, Su X. Jmjd3/IRF4 axis aggravates myeloid fibroblast activation and m2 macrophage to myofibroblast transition in renal fibrosis. Front Immunol 2022; 13:978262. [PMID: 36159833 PMCID: PMC9494509 DOI: 10.3389/fimmu.2022.978262] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 08/16/2022] [Indexed: 11/13/2022] Open
Abstract
Renal fibrosis commonly occurs in the process of chronic kidney diseases. Here, we explored the role of Jumonji domain containing 3 (Jmjd3)/interferon regulatory factor 4 (IRF4) axis in activation of myeloid fibroblasts and transition of M2 macrophages into myofibroblasts transition (M2MMT) in kidney fibrosis. In mice, Jmjd3 and IRF4 were highly induced in interstitial cells of kidneys with folic acid or obstructive injury. Jmjd3 deletion in myeloid cells or Jmjd3 inhibitor reduced the levels of IRF4 in injured kidneys. Myeloid Jmjd3 depletion impaired bone marrow-derived fibroblasts activation and M2MMT in folic acid or obstructive nephropathy, resulting in reduction of extracellular matrix (ECM) proteins expression, myofibroblasts formation and renal fibrosis progression. Pharmacological inhibition of Jmjd3 also prevented myeloid fibroblasts activation, M2MMT, and kidney fibrosis development in folic acid nephropathy. Furthermore, IRF4 disruption inhibited myeloid myofibroblasts accumulation, M2MMT, ECM proteins accumulation, and showed milder fibrotic response in obstructed kidneys. Bone marrow transplantation experiment showed that wild-type mice received IRF4-/- bone marrow cells presented less myeloid fibroblasts activation in injured kidneys and exhibited much less kidney fibrosis after unilateral ureteral obstruction. Myeloid Jmjd3 deletion or Jmjd3 inhibitor attenuated expressions of IRF4, α-smooth muscle actin and fibronectin and impeded M2MMT in cultured monocytes exposed to IL-4. Conversely, overexpression IRF4 abrogated the effect of myeloid Jmjd3 deletion on M2MMT. Thus, Jmjd3/IRF4 signaling has a crucial role in myeloid fibroblasts activation, M2 macrophages to myofibroblasts transition, extracellular matrix protein deposition, and kidney fibrosis progression.
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Affiliation(s)
- Hua Liang
- Department of Anesthesiology, Foshan Women and Children Hospital, Foshan, China
- Department of Anesthesiology, Affiliated Foshan Women and Children Hospital of Southern Medical University, Foshan, China
| | - Benquan Liu
- Department of Anesthesiology, The First People’s Hospital of Foshan, Foshan, China
| | - Ying Gao
- Department of Anesthesiology, The First People’s Hospital of Foshan, Foshan, China
| | - Jiayi Nie
- Department of Anesthesiology, The First People’s Hospital of Foshan, Foshan, China
| | - Shuyun Feng
- Department of Anesthesiology, The First People’s Hospital of Foshan, Foshan, China
| | - Wenqiang Yu
- Department of Anesthesiology, The First People’s Hospital of Foshan, Foshan, China
- *Correspondence: Wenqiang Yu, ; Xi Su,
| | - Shihong Wen
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Xi Su
- Department of Paediatrics, Foshan Women and Children Hospital, Foshan, China
- *Correspondence: Wenqiang Yu, ; Xi Su,
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Critical Roles of Polycomb Repressive Complexes in Transcription and Cancer. Int J Mol Sci 2022; 23:ijms23179574. [PMID: 36076977 PMCID: PMC9455514 DOI: 10.3390/ijms23179574] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 11/17/2022] Open
Abstract
Polycomp group (PcG) proteins are members of highly conserved multiprotein complexes, recognized as gene transcriptional repressors during development and shown to play a role in various physiological and pathological processes. PcG proteins consist of two Polycomb repressive complexes (PRCs) with different enzymatic activities: Polycomb repressive complexes 1 (PRC1), a ubiquitin ligase, and Polycomb repressive complexes 2 (PRC2), a histone methyltransferase. Traditionally, PRCs have been described to be associated with transcriptional repression of homeotic genes, as well as gene transcription activating effects. Particularly in cancer, PRCs have been found to misregulate gene expression, not only depending on the function of the whole PRCs, but also through their separate subunits. In this review, we focused especially on the recent findings in the transcriptional regulation of PRCs, the oncogenic and tumor-suppressive roles of PcG proteins, and the research progress of inhibitors targeting PRCs.
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27
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Liu Y, Chen C, Wang X, Sun Y, Zhang J, Chen J, Shi Y. An Epigenetic Role of Mitochondria in Cancer. Cells 2022; 11:cells11162518. [PMID: 36010594 PMCID: PMC9406960 DOI: 10.3390/cells11162518] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/03/2022] [Accepted: 08/09/2022] [Indexed: 12/14/2022] Open
Abstract
Mitochondria are not only the main energy supplier but are also the cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD+, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which are the main substrates for DNA methylation and histone post-translation modifications, essential for gene transcriptional regulation and cell fate determination. Tumorigenesis is attributed to many factors, including gene mutations and tumor microenvironment. Mitochondria and epigenetics play essential roles in tumor initiation, evolution, metastasis, and recurrence. Targeting mitochondrial metabolism and epigenetics are promising therapeutic strategies for tumor treatment. In this review, we summarize the roles of mitochondria in key metabolites required for epigenetics modification and in cell fate regulation and discuss the current strategy in cancer therapies via targeting epigenetic modifiers and related enzymes in metabolic regulation. This review is an important contribution to the understanding of the current metabolic-epigenetic-tumorigenesis concept.
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Affiliation(s)
- Yu’e Liu
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Chao Chen
- Department of Neurosurgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China
| | - Xinye Wang
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yihong Sun
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jin Zhang
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Juxiang Chen
- Department of Neurosurgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China
- Correspondence: (J.C.); (Y.S.)
| | - Yufeng Shi
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai 200092, China
- Correspondence: (J.C.); (Y.S.)
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28
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Abu-Hanna J, Patel JA, Anastasakis E, Cohen R, Clapp LH, Loizidou M, Eddama MMR. Therapeutic potential of inhibiting histone 3 lysine 27 demethylases: a review of the literature. Clin Epigenetics 2022; 14:98. [PMID: 35915507 PMCID: PMC9344682 DOI: 10.1186/s13148-022-01305-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 07/03/2022] [Indexed: 11/16/2022] Open
Abstract
Histone 3 lysine 27 (H3K27) demethylation constitutes an important epigenetic mechanism of gene activation. It is mediated by the Jumonji C domain-containing lysine demethylases KDM6A and KDM6B, both of which have been implicated in a wide myriad of diseases, including blood and solid tumours, autoimmune and inflammatory disorders, and infectious diseases. Here, we review and summarise the pre-clinical evidence, both in vitro and in vivo, in support of the therapeutic potential of inhibiting H3K27-targeting demethylases, with a focus on the small-molecule inhibitor GSK-J4. In malignancies, KDM6A/B inhibition possesses the ability to inhibit proliferation, induce apoptosis, promote differentiation, and heighten sensitivity to currently employed chemotherapeutics. KDM6A/B inhibition also comprises a potent anti-inflammatory approach in inflammatory and autoimmune disorders associated with inappropriately exuberant inflammatory and autoimmune responses, restoring immunological homeostasis to inflamed tissues. With respect to infectious diseases, KDM6A/B inhibition can suppress the growth of infectious pathogens and attenuate the immunopathology precipitated by these pathogens. The pre-clinical in vitro and in vivo data, summarised in this review, suggest that inhibiting H3K27 demethylases holds immense therapeutic potential in many diseases.
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Affiliation(s)
- Jeries Abu-Hanna
- Division of Surgery and Interventional Science, Research Department of Surgical Biotechnology, University College London, GI Services, Ground Floor, 250 Euston Road, London, NW1 2PG, UK
| | - Jigisha A Patel
- Division of Surgery and Interventional Science, Research Department of Surgical Biotechnology, University College London, GI Services, Ground Floor, 250 Euston Road, London, NW1 2PG, UK
| | | | - Richard Cohen
- Division of Surgery and Interventional Science, Research Department of Surgical Biotechnology, University College London, GI Services, Ground Floor, 250 Euston Road, London, NW1 2PG, UK.,Department of Gastroenterology, University College London Hospital, London, UK
| | - Lucie H Clapp
- Institute of Cardiovascular Science, University College London, London, UK
| | - Marilena Loizidou
- Division of Surgery and Interventional Science, Research Department of Surgical Biotechnology, University College London, GI Services, Ground Floor, 250 Euston Road, London, NW1 2PG, UK
| | - Mohammad M R Eddama
- Division of Surgery and Interventional Science, Research Department of Surgical Biotechnology, University College London, GI Services, Ground Floor, 250 Euston Road, London, NW1 2PG, UK. .,Department of Gastroenterology, University College London Hospital, London, UK.
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Park J, Lee K, Kim K, Yi SJ. The role of histone modifications: from neurodevelopment to neurodiseases. Signal Transduct Target Ther 2022; 7:217. [PMID: 35794091 PMCID: PMC9259618 DOI: 10.1038/s41392-022-01078-9] [Citation(s) in RCA: 130] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/11/2022] [Accepted: 06/21/2022] [Indexed: 12/24/2022] Open
Abstract
Epigenetic regulatory mechanisms, including DNA methylation, histone modification, chromatin remodeling, and microRNA expression, play critical roles in cell differentiation and organ development through spatial and temporal gene regulation. Neurogenesis is a sophisticated and complex process by which neural stem cells differentiate into specialized brain cell types at specific times and regions of the brain. A growing body of evidence suggests that epigenetic mechanisms, such as histone modifications, allow the fine-tuning and coordination of spatiotemporal gene expressions during neurogenesis. Aberrant histone modifications contribute to the development of neurodegenerative and neuropsychiatric diseases. Herein, recent progress in understanding histone modifications in regulating embryonic and adult neurogenesis is comprehensively reviewed. The histone modifications implicated in neurodegenerative and neuropsychiatric diseases are also covered, and future directions in this area are provided.
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Affiliation(s)
- Jisu Park
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyubin Lee
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyunghwan Kim
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
| | - Sun-Ju Yi
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
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30
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Ma S, Xu L, Chen L, Sun X, Hu F, Gong Y, Yang R, Li J, Wang Q, Huang S, Zhou H, Wang J. Novel pharmacological inhibition of JMJD3 improves necrotizing enterocolitis by attenuating the inflammatory response and ameliorating intestinal injury. Biochem Pharmacol 2022; 203:115165. [PMID: 35803318 DOI: 10.1016/j.bcp.2022.115165] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/15/2022] [Accepted: 06/28/2022] [Indexed: 11/15/2022]
Abstract
Necrotizing enterocolitis (NEC), an acute intestinal inflammatory disease of premature infants, is one of the leading causes of death in neonates. Effective measures for clinical treatment are limited and there is a pressing need in searching for new therapeutic strategies. Jumonji domain-containing protein D3 (JMJD3), a histone H3 lysine 27 (H3K27) demethylase plays a proinflammatory role in sepsis and neuroinflammation. However, whether JMJD3 is involved in the pathogenesis of NEC has not been elucidated. Here we report that overexpressed JMJD3 was revealed in the intestine of NEC patients by bioinformatic analysis. Moreover, upregulated JMJD3 and suppressed H3K27me3 were detected in both NEC patients and neonatal mice subjected to experimental NEC. Importantly, administration of GSK-J4, a specific JMJD3 inhibitor, rescued neonatal mice from NEC-associated lethality by suppressing proinflammatory response with attenuated IL-6, TNF-α, and MCP-1 levels and ameliorating intestinal injury with reversed claudin-1, occludin, and E-cadherin expression. Remarkably, administration of GSK-J4 attenuated intestinal injury by inhibiting activation of intestinal necroptosis in NEC mice. Administration of GSK-J4 regulated intestinal inflammation via NF-κB and JAK2/STAT3 pathway. These results indicate that JMJD3 is involved in the development of NEC and inhibition of JMJD3 overexpression by mean of GSK-J4 could be a potential therapeutic approach in the prevention and treatment of NEC.
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Affiliation(s)
- Shurong Ma
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Lingqi Xu
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Lulu Chen
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Xu Sun
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Fangjie Hu
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Yuan Gong
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Randong Yang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Jing Li
- Department of Surgery, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Qian Wang
- Department of Anesthesiology, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Shungen Huang
- Department of Surgery, Children's Hospital of Soochow University, Suzhou 215025, China
| | - Huiting Zhou
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou 215025, China.
| | - Jian Wang
- Department of Surgery, Children's Hospital of Soochow University, Suzhou 215025, China.
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Yang J, Hu Y, Zhang B, Liang X, Li X. The JMJD Family Histone Demethylases in Crosstalk Between Inflammation and Cancer. Front Immunol 2022; 13:881396. [PMID: 35558079 PMCID: PMC9090529 DOI: 10.3389/fimmu.2022.881396] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/23/2022] [Indexed: 02/05/2023] Open
Abstract
Inflammation has emerged as a key player in regulating cancer initiation, progression, and therapeutics, acting as a double edged sword either facilitating cancer progression and therapeutic resistance or inducing anti-tumor immune responses. Accumulating evidence has linked the epigenetic modifications of histones to inflammation and cancer, and histone modifications-based strategies have shown promising therapeutic potentials against cancer. The jumonji C domain-containing (JMJD) family histone demethylases have exhibited multiple regulator functions in inflammatory processes and cancer development, and a number of therapeutic strategies targeting JMJD histone demethylases to modulate inflammatory cells and their products have been successfully evaluated in clinical or preclinical tumor models. This review summarizes current understanding of the functional roles and mechanisms of JMJD histone demethylases in crosstalk between inflammation and cancer, and highlights recent clinical and preclinical progress on harnessing the JMJD histone demethylases to regulate cancer-related inflammation for future cancer therapeutics.
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Affiliation(s)
- Jia Yang
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Yuan Hu
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Binjing Zhang
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiao Liang
- Department of Gynecology and Obstetrics and Pediatric Nephrology Nursing, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xin Li
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Roy S, Sinha N, Huang B, Cline-Fedewa H, Gleicher N, Wang J, Sen A. Jumonji Domain-containing Protein-3 (JMJD3/Kdm6b) Is Critical for Normal Ovarian Function and Female Fertility. Endocrinology 2022; 163:6565906. [PMID: 35396990 PMCID: PMC9070484 DOI: 10.1210/endocr/bqac047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Indexed: 11/19/2022]
Abstract
In females, reproductive success is dependent on the expression of a number of genes regulated at different levels, one of which is through epigenetic modulation. How a specific epigenetic modification regulates gene expression and their downstream effect on ovarian function are important for understanding the female reproductive process. The trimethylation of histone3 at lysine27 (H3K27me3) is associated with gene repression. JMJD3 (or KDM6b), a jumonji domain-containing histone demethylase specifically catalyzes the demethylation of H3K27me3, that positively influences gene expression. This study reports that the expression of JMJD3 specifically in the ovarian granulosa cells (GCs) is critical for maintaining normal female fertility. Conditional deletion of Jmjd3 in the GCs results in a decreased number of total healthy follicles, disrupted estrous cycle, and increased follicular atresia culminating in subfertility and premature ovarian failure. At the molecular level, the depletion of Jmjd3 and RNA-seq analysis reveal that JMJD3 is essential for mitochondrial function. JMJD3-mediated reduction of H3K27me3 induces the expression of Lif (Leukemia inhibitory factor) and Ctnnb1 (β-catenin), that in turn regulate the expression of key mitochondrial genes critical for the electron transport chain. Moreover, mitochondrial DNA content is also significantly decreased in Jmjd3 null GCs. Additionally, we have uncovered that the expression of Jmjd3 in GCs decreases with age, both in mice and in humans. Thus, in summary, our studies highlight the critical role of JMJD3 in nuclear-mitochondrial genome coordination that is essential for maintaining normal ovarian function and female fertility and underscore a potential role of JMJD3 in female reproductive aging.
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Affiliation(s)
- Sambit Roy
- Reproductive and Developmental Sciences Program, Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA
| | - Niharika Sinha
- Reproductive and Developmental Sciences Program, Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA
| | - Binbin Huang
- Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - Holly Cline-Fedewa
- Reproductive and Developmental Sciences Program, Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA
| | | | - Jianrong Wang
- Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - Aritro Sen
- Reproductive and Developmental Sciences Program, Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA
- Correspondence: Aritro Sen, PhD, Reproductive and Developmental Sciences Program, Department of Animal Sciences, 766 Service Rd, Interdisciplinary Science & Technology Building, Michigan State University, East Lansing, MI 48824, USA.
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33
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Structural Bioinformatics Enhances the Interpretation of Somatic Mutations in KDM6A Found in Human Cancers. Comput Struct Biotechnol J 2022; 20:2200-2211. [PMID: 35615018 PMCID: PMC9111933 DOI: 10.1016/j.csbj.2022.04.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/18/2022] [Accepted: 04/18/2022] [Indexed: 11/24/2022] Open
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34
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Insa Pineda I, Gómez González CL. The KDM6B mutation: Phenotype and clinical characteristics-Report of a case. REVISTA DE PSIQUIATRIA Y SALUD MENTAL 2022; 15:88-93. [PMID: 35840288 DOI: 10.1016/j.rpsmen.2022.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 12/21/2020] [Indexed: 06/15/2023]
Abstract
INTRODUCTION Alterations in the genes of lysine methylation as Lysine-specific demethylase 6B (KDM6B) have been associated with multiple neurodevelopmental disorders. Until now, there are few cases in the literature attributed to KDM6B mutations. This gap may be due to the fact that the exome sequencing technique is still being implemented in routine clinical practice. MATERIAL AND METHODS A case is presented with its clinical and phenotypic characteristics. The sequence exome analysis was done with the Nimblegen SeqCap EZ MedExome capture kit+mtDNA 47Mb. The psychopathological approach from mental health was carried out through individual and family interviews, the Conner's questionnaires, ADHD rating scale, as well as the psychometry. RESULTS A frameshift variant in the KDM6B gene related to neurodevelopmental disorders with facial and body dysmorphia was obtained. The case was oriented as a neurodevelopmental disorder secondary to a genetic alteration and a comorbid Attention Deficit Hyperactivity Disorder (ADHD). CONCLUSIONS The clinical peculiarities shared by patients identified with the KDM6B mutation, raises the need to recognize it as a particular entity. The possibility of applying the exome sequencing technique to patients with syndromic phenotype and developmental impairment may clarify its etiopathogenesis. It is highly probable that the complexity of these cases requires an approach by a multidisciplinary team that includes genetics, neurology and psychiatry, among other specialties. The coordinated approach is essential to have a comprehensive vision of the case.
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Affiliation(s)
- Inmaculada Insa Pineda
- Child and Adolescent Psychiatry and Psychology, Department of Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain; Children and Adolescent Mental Health Research Group (Consolidated group 2017 SGR 964), Institut de Recerca Sant Joan de Déu, Spain.
| | - Cristina Luz Gómez González
- Child and Adolescent Psychiatry and Psychology, Department of Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
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35
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Tsuda S, Pipkin ME. Transcriptional Control of Cell Fate Determination in Antigen-Experienced CD8 T Cells. Cold Spring Harb Perspect Biol 2022; 14:a037945. [PMID: 34127445 PMCID: PMC8805646 DOI: 10.1101/cshperspect.a037945] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Robust immunity to intracellular infections is mediated by antigen-specific naive CD8 T cells that become activated and differentiate into phenotypically and functionally diverse subsets of effector cells, some of which terminally differentiate and others that give rise to memory cells that provide long-lived protection. This developmental system is an outstanding model with which to elucidate how regulation of chromatin structure and transcriptional control establish gene expression programs that govern cell fate determination, insights from which are likely to be useful for informing the design of immunotherapeutic approaches to engineer durable immunity to infections and tumors. A unifying framework that describes how naive CD8 T cells develop into memory cells is still outstanding. We propose a model that incorporates a common early linear path followed by divergent paths that slowly lose capacity to interconvert and discuss classical and contemporary observations that support these notions, focusing on insights from transcriptional control and chromatin regulation.
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Affiliation(s)
- Shanel Tsuda
- Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida 33458, USA
| | - Matthew E Pipkin
- Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida 33458, USA
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36
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Zhang P, Guergues J, Alleyne AR, Cirino TJ, Nadeau O, Figueroa AM, Stacy HM, Suzuki T, McLaughlin JP, Stevens SM, Liu B. Novel Histone Modifications in Microglia Derived from a Mouse Model of Chronic Pain. Proteomics 2022; 22:e2100137. [PMID: 35081661 DOI: 10.1002/pmic.202100137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 11/06/2022]
Abstract
As the resident immune cells in the central nervous system, microglia play an important role in the maintenance of its homeostasis. Dysregulation of microglia has been associated with the development and maintenance of chronic pain. However, the relevant molecular pathways remain poorly defined. In this study, we used a mass spectrometry-based proteomic approach to screen potential changes of histone protein modifications in microglia isolated from the brain of control and cisplatin-induced neuropathic pain adult C57BL/6J male mice. We identified several novel microglial histone modifications associated with pain including statistically significantly decreased histone H3.1 lysine 27 mono-methylation (H3.1K27me1, 54.8% of control) and lysine 56 tri-methylation (7.5% of control), as well as a trend suggesting increased histone 3 tyrosine 41 nitration. We further investigated the functional role of H3.1K27me1 and found that treatment of cultured microglial cells for 4 consecutive days with 1-10 μM of NCDM-64, a potent and selective inhibitor of lysine demethylase 7A, an enzyme responsible for the demethylation of H3K27me1, dose-dependently elevated its levels with a greater than a 2-fold increase observed at 10 μM compared to vehicle-treated control cells. Moreover, pre-treatment of mice with NCDM-64 (10 or 25 mg/kg/day, i.p.) prior to cisplatin treatment prevented the development of neuropathic pain in mice. The identification of specific chromatin marks in microglia associated with chronic pain may yield critical insight into the contribution of microglia to the development and maintenance of pain, and opens new avenues for the development of novel non-opioid therapeutics for the effective management of chronic pain. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Ping Zhang
- Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA
| | - Jennifer Guergues
- Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, USA
| | - Amy R Alleyne
- Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA
| | - Thomas J Cirino
- Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA
| | - Owen Nadeau
- Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT, USA
| | - Ariana M Figueroa
- Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA
| | - Heather M Stacy
- Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA
| | - Takayoshi Suzuki
- The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan
| | - Jay P McLaughlin
- Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA
| | - Stanley M Stevens
- Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, USA
| | - Bin Liu
- Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA
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37
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The ERα/KDM6B regulatory axis modulates osteogenic differentiation in human mesenchymal stem cells. Bone Res 2022; 10:3. [PMID: 34992221 PMCID: PMC8738748 DOI: 10.1038/s41413-021-00171-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/11/2021] [Accepted: 08/02/2021] [Indexed: 01/19/2023] Open
Abstract
Osteoporosis is a highly prevalent public health burden associated with an increased risk of bone fracture, particularly in aging women. Estrogen, an important medicinal component for the preventative and therapeutic treatment of postmenopausal osteoporosis, induces osteogenesis by activating the estrogen receptor signaling pathway and upregulating the expression of osteogenic genes, such as bone morphogenetic proteins (BMPs). The epigenetic regulation of estrogen-mediated osteogenesis, however, is still unclear. In this report, we found that estrogen significantly induced the expression of lysine-specific demethylase 6B (KDM6B) and that KDM6B depletion by shRNAs led to a significant reduction in the osteogenic potential of DMSCs. Mechanistically, upon estrogen stimulation, estrogen receptor-α (ERα) was recruited to the KDM6B promoter, directly enhancing KDM6B expression. Subsequently, KDM6B was recruited to the BMP2 and HOXC6 promoters, resulting in the removal of H3K27me3 marks and activating the transcription of BMP2 and HOXC6, the master genes of osteogenic differentiation. Furthermore, we found that estrogen enhanced DMSC osteogenesis during calvarial bone regeneration and that estrogen's pro-osteogenic effect was dependent on KDM6B in vivo. Taken together, our results demonstrate the vital role of the ERα/KDM6B regulatory axis in the epigenetic regulation of the estrogen-dependent osteogenic response.
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38
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Liu Y, Gan L, Cui DX, Yu SH, Pan Y, Zheng LW, Wan M. Epigenetic regulation of dental pulp stem cells and its potential in regenerative endodontics. World J Stem Cells 2021; 13:1647-1666. [PMID: 34909116 PMCID: PMC8641018 DOI: 10.4252/wjsc.v13.i11.1647] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 06/07/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023] Open
Abstract
Regenerative endodontics (RE) therapy means physiologically replacing damaged pulp tissue and regaining functional dentin–pulp complex. Current clinical RE procedures recruit endogenous stem cells from the apical papilla, periodontal tissue, bone marrow and peripheral blood, with or without application of scaffolds and growth factors in the root canal space, resulting in cementum-like and bone-like tissue formation. Without the involvement of dental pulp stem cells (DPSCs), it is unlikely that functional pulp regeneration can be achieved, even though acceptable repair can be acquired. DPSCs, due to their specific odontogenic potential, high proliferation, neurovascular property, and easy accessibility, are considered as the most eligible cell source for dentin–pulp regeneration. The regenerative potential of DPSCs has been demonstrated by recent clinical progress. DPSC transplantation following pulpectomy has successfully reconstructed neurovascularized pulp that simulates the physiological structure of natural pulp. The self-renewal, proliferation, and odontogenic differentiation of DPSCs are under the control of a cascade of transcription factors. Over recent decades, epigenetic modulations implicating histone modifications, DNA methylation, and noncoding (nc)RNAs have manifested as a new layer of gene regulation. These modulations exhibit a profound effect on the cellular activities of DPSCs. In this review, we offer an overview about epigenetic regulation of the fate of DPSCs; in particular, on the proliferation, odontogenic differentiation, angiogenesis, and neurogenesis. We emphasize recent discoveries of epigenetic molecules that can alter DPSC status and promote pulp regeneration through manipulation over epigenetic profiles.
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Affiliation(s)
- Ying Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lu Gan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Di-Xin Cui
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Si-Han Yu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yue Pan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Li-Wei Zheng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Mian Wan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
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39
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VanRyzin JW. Phagocytic microglia in development: Are they what they eat? Brain Behav Immun Health 2021; 18:100373. [PMID: 34761244 PMCID: PMC8566956 DOI: 10.1016/j.bbih.2021.100373] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 09/29/2021] [Accepted: 10/13/2021] [Indexed: 12/30/2022] Open
Abstract
Microglia, the innate immune cells of the brain, are indispensable for proper brain development. As professional phagocytes, microglia engulf other cells within distinct developmental niches to sculpt the architecture of the brain. Here, I highlight the age-, brain region-, and substrate-dependent diversity of developmental phagocytosis, and pose the idea that phagocytosis may, in turn, drive changes in microglia phenotype. Ultimately, phagocytosis might be just as important for shaping microglia function as it is for shaping the brain.
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Affiliation(s)
- Jonathan W VanRyzin
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, United States
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40
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Li L, Bai L, Yang K, Zhang J, Gao Y, Jiang M, Yang Y, Zhang X, Wang L, Wang X, Qiao Y, Xu JT. KDM6B epigenetically regulated-interleukin-6 expression in the dorsal root ganglia and spinal dorsal horn contributes to the development and maintenance of neuropathic pain following peripheral nerve injury in male rats. Brain Behav Immun 2021; 98:265-282. [PMID: 34464689 DOI: 10.1016/j.bbi.2021.08.231] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 08/17/2021] [Accepted: 08/21/2021] [Indexed: 12/20/2022] Open
Abstract
The lysine specific demethylase 6B (KDM6B) has been implicated as a coregulator in the expression of proinflammatory mediators, and in the pathogenesis of inflammatory and arthritic pain. However, the role of KDM6B in neuropathic pain has yet to be studied. In the current study, the neuropathic pain was determined by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) following lumbar 5 spinal nerve ligation (SNL) in male rats. Immunohistochemistry, Western blotting, qRT-PCR, and chromatin immunoprecipitation (ChIP)-PCR assays were performed to investigate the underlying mechanisms. Our results showed that SNL led to a significant increase in KDM6B mRNA and protein in the ipsilateral L4/5 dorsal root ganglia (DRG) and spinal dorsal horn; and this increase correlated a markedly reduction in the level of H3K27me3 methylation in the same tissue. Double immunofluorescence staining revealed that the KDM6B expressed in myelinated A- and unmyelinated C-fibers in the DRG; and located in neuronal cells, astrocytes, and microglia in the dorsal horn. Behavioral data showed that SNL-induced mechanical allodynia and thermal hyperalgesia were impaired by the treatment of prior to i.t. injection of GSK-J4, a specific inhibitor of KDM6B, or KDM6B siRNA. Both microinjection of AAV2-EGFP-KDM6B shRNA in the lumbar 5 dorsal horn and sciatic nerve, separately, alleviated the neuropathic pain following SNL. The established neuropathic pain was also partially attenuated by repeat i.t. injections of GSK-J4 or KDM6B siRNA, started on day 7 after SNL. SNL also resulted in a remarkable increased expression of interleukin-6 (IL-6) in the DRG and dorsal horn. But this increase was dramatically inhibited by i.t. injection of GSK-J4 and KDM6B siRNA; and suppressed by prior to microinjection of AAV2-EGFP-KDM6B shRNA in the dorsal horn and sciatic nerve. Results of ChIP-PCR assay showed that SNL-induced enhanced binding of STAT3 with IL-6 promoter was inhibited by prior to i.t. injection of GSK-J4. Meanwhile, the level of H3K27me3 methylation was also decreased by the treatment. Together, our results indicate that SNL-induced upregulation of KDM6B via demethylating H3K27me3 facilitates the binding of STAT3 with IL-6 promoter, and subsequently mediated-increase in the expression of IL-6 in the DRG and dorsal horn contributes to the development and maintenance of neuropathic pain. Targeting KDM6B might a promising therapeutic strategy to treatment of chronic pain.
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Affiliation(s)
- Liren Li
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Liying Bai
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China; Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China
| | - Kangli Yang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China; Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital, Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China
| | - Jian Zhang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Yan Gao
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China; Neuroscience Research Institute, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Mingjun Jiang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Yin Yang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Xuan Zhang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Li Wang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Xueli Wang
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Yiming Qiao
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China
| | - Ji-Tian Xu
- Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China; Neuroscience Research Institute, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China.
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Nguyen K, Dobrowolski C, Shukla M, Cho WK, Luttge B, Karn J. Inhibition of the H3K27 demethylase UTX enhances the epigenetic silencing of HIV proviruses and induces HIV-1 DNA hypermethylation but fails to permanently block HIV reactivation. PLoS Pathog 2021; 17:e1010014. [PMID: 34673825 PMCID: PMC8562785 DOI: 10.1371/journal.ppat.1010014] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 11/02/2021] [Accepted: 10/07/2021] [Indexed: 01/09/2023] Open
Abstract
One strategy for a functional cure of HIV-1 is "block and lock", which seeks to permanently suppress the rebound of quiescent HIV-1 by epigenetic silencing. For the bivalent promoter in the HIV LTR, both histone 3 lysine 27 tri-methylation (H3K27me3) and DNA methylation are associated with viral suppression, while H3K4 tri-methylation (H3K4me3) is correlated with viral expression. However, H3K27me3 is readily reversed upon activation of T-cells through the T-cell receptor. In an attempt to suppress latent HIV-1 in a stable fashion, we knocked down the expression or inhibited the activity of UTX/KDM6A, the major H3K27 demethylase, and investigated its impact on latent HIV-1 reactivation in T cells. Inhibition of UTX dramatically enhanced H3K27me3 levels at the HIV LTR and was associated with increased DNA methylation. In latently infected cells from patients, GSK-J4, which is a potent dual inhibitor of the H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A, effectively suppressed the reactivation of latent HIV-1 and also induced DNA methylation at specific sites in the 5'LTR of latent HIV-1 by the enhanced recruitment of DNMT3A to HIV-1. Nonetheless, suppression of HIV-1 through epigenetic silencing required the continued treatment with GSK-J4 and was rapidly reversed after removal of the drug. DNA methylation was also rapidly lost after removal of drug, suggesting active and rapid DNA-demethylation of the HIV LTR. Thus, induction of epigenetic silencing by histone and DNA methylation appears to be insufficient to permanently silence HIV-1 proviral transcription.
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Affiliation(s)
- Kien Nguyen
- Department of Molecular Biology and Microbiology, Case Western Reserve University Medical School, Cleveland, Ohio, United States of America
| | - Curtis Dobrowolski
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, Georgia, United States of America
| | - Meenakshi Shukla
- Department of Molecular Biology and Microbiology, Case Western Reserve University Medical School, Cleveland, Ohio, United States of America
| | - Won-Kyung Cho
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Dong-gu, Daegu, Republic of Korea
| | - Benjamin Luttge
- Department of Molecular Biology and Microbiology, Case Western Reserve University Medical School, Cleveland, Ohio, United States of America
| | - Jonathan Karn
- Department of Molecular Biology and Microbiology, Case Western Reserve University Medical School, Cleveland, Ohio, United States of America
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42
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The progress of research on histone methylation in ischemic stroke pathogenesis. J Physiol Biochem 2021; 78:1-8. [PMID: 34472033 DOI: 10.1007/s13105-021-00841-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 08/16/2021] [Indexed: 10/20/2022]
Abstract
Stroke, also known as cerebral stroke or cerebrovascular accident, refers to acute ischemic or hemorrhagic encephalopathy caused by a disturbance to cerebral blood flow. Ischemic stroke is the most common type of cerebral stroke, accounting for approximately 80% of the total incidence of clinical stroke. High morbidity, disability, and mortality rates place heavy burdens on the families of patients and society. An increasing number of studies have shown that histone modification plays an important role in the pathogenesis of ischemic stroke, but most studies on histone modification focus on acetylation, and studies on the role of histone methylation in the pathogenesis of ischemic stroke are limited. Here, we review the role of histone methylation and related histone methyltransferase (HMT) inhibitors in the pathogenesis of ischemic stroke and related HMT inhibitors in the treatment of ischemic stroke, which may open up a new avenue to the study of ischemic stroke.
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43
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Xun J, Gao R, Wang B, Li Y, Ma Y, Guan J, Zhang Q. Histone demethylase KDM6B inhibits breast cancer metastasis by regulating Wnt/β-catenin signaling. FEBS Open Bio 2021. [PMID: 34165914 PMCID: PMC8329947 DOI: 10.1002/2211-5463.13236] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/06/2021] [Accepted: 06/23/2021] [Indexed: 01/22/2023] Open
Abstract
Tumor metastasis remains a major challenge for patients with breast cancer. Aberrant epigenetic factor lysine‐specific demethylase 6B (KDM6B) has been associated with tumor progression. Here, we show that KDM6B is significantly down‐regulated in human breast cancer tissues, and its low expression is associated with poor prognosis of patients with breast cancer. Furthermore, overexpression of KDM6B remarkably inhibited cell proliferation, invasion, migration and epithelial–mesenchymal transition markers of breast cancer cells in vitro and tumor growth and lung metastasis in vivo. Notably, the expression of KDM6B in breast cancer tissues was negatively correlated with that of β‐catenin, and overexpression of KDM6B decreased the expression of β‐catenin and its accumulation in the nucleus of breast cancer cells. Overall, our findings provide novel insights into suppression of metastasis of breast cancer cells by KDM6B via β‐catenin and suggest involvement of the KDM6B‐Wnt/β‐catenin axis in breast cancer progression.
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Affiliation(s)
- Jing Xun
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, China
| | - Ruifang Gao
- Tianjin Institute of Medical & Pharmaceutical Sciences, Tianjin, China
| | - Botao Wang
- Graduate School of Tianjin Medical University, China
| | - Yifan Li
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Integrated Chinese and Western Medicine Hospital, Tianjin University, China
| | - Yuan Ma
- Graduate School of Tianjin Medical University, China
| | - Jun Guan
- Graduate School of Tianjin Medical University, China
| | - Qi Zhang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Integrated Chinese and Western Medicine Hospital, Tianjin University, China
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44
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Qin M, Han F, Wu J, Gao FX, Li Y, Yan DX, He XM, Long Y, Tang XP, Ren DL, Gao Y, Dai TY. KDM6B promotes ESCC cell proliferation and metastasis by facilitating C/EBPβ transcription. BMC Cancer 2021; 21:559. [PMID: 34001062 PMCID: PMC8130268 DOI: 10.1186/s12885-021-08282-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/26/2021] [Indexed: 12/24/2022] Open
Abstract
Background As an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression, KDM6B has been implicated in the development and malignant progression in various types of cancers. However, its potential roles in esophageal squamous cell carcinoma (ESCC) have not been explored. Methods The expression of KDM6B in human ESCC tissues and cell lines was examined using RT-qPCR, immunohistochemical staining and immunoblotting. The effects of KDM6B on the proliferation and metastasis of ESCC were examined using in vitro and in vivo functional tests. RNA-seq and ChIP-seq assay were used to demonstrate the molecular biological mechanism of KDM6B in ESCC. Results We show that the expression level of KDM6B increased significantly in patients with lymph node metastasis. Furthermore, we confirmed that KDM6B knockdown reduces proliferation and metastasis of ESCC cells, while KDM6B overexpression has the opposite effects. Mechanistically, KDM6B regulates TNFA_SIGNALING_VIA_NFκB signalling pathways, and H3K27me3 binds to the promoter region of C/EBPβ, leading to the promotion of C/EBPβ transcription. Besides, we show that GSK-J4, a chemical inhibitor of KDM6B, markedly inhibits proliferation and metastasis of ESCC cells. Conclusions The present study demonstrated that KDM6B promotes ESCC progression by increasing the transcriptional activity of C/EBPβ depending on its H3K27 demethylase activity. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08282-w.
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Affiliation(s)
- Mei Qin
- Department of Immunology, Basic Medicine College, South West Medical University, Luzhou, Sichuan, China
| | - Fei Han
- Department of Thoracic Surgery, The Affiliated Hospital of Southwest, Medical University, Sichuan, Luzhou, China
| | - Jian Wu
- Department of Thoracic Surgery, The Affiliated Hospital of Southwest, Medical University, Sichuan, Luzhou, China
| | - Feng-Xia Gao
- Department of Immunology, Basic Medicine College, South West Medical University, Luzhou, Sichuan, China
| | - Yuan Li
- Department of Thoracic Surgery, The Affiliated Hospital of Southwest, Medical University, Sichuan, Luzhou, China
| | - De-Xin Yan
- Department of Thoracic Surgery, The Affiliated Hospital of Southwest, Medical University, Sichuan, Luzhou, China
| | - Xue-Mei He
- Experimental Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yang Long
- Experimental Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Xiao-Ping Tang
- Experimental Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - De-Lian Ren
- Department of Immunology, Basic Medicine College, South West Medical University, Luzhou, Sichuan, China
| | - Yan Gao
- Department of Immunology, Basic Medicine College, South West Medical University, Luzhou, Sichuan, China.
| | - Tian-Yang Dai
- Department of Thoracic Surgery, The Affiliated Hospital of Southwest, Medical University, Sichuan, Luzhou, China.
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Wan C, Zhang F, Yao H, Li H, Tuan RS. Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications. Front Cell Dev Biol 2021; 9:626708. [PMID: 33937229 PMCID: PMC8085601 DOI: 10.3389/fcell.2021.626708] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/17/2021] [Indexed: 12/12/2022] Open
Abstract
The involvement of histone modifications in cartilage development, pathology and regeneration is becoming increasingly evident. Understanding the molecular mechanisms and consequences of histone modification enzymes in cartilage development, homeostasis and pathology provides fundamental and precise perspectives to interpret the biological behavior of chondrocytes during skeletal development and the pathogenesis of various cartilage related diseases. Candidate molecules or drugs that target histone modifying proteins have shown promising therapeutic potential in the treatment of cartilage lesions associated with joint degeneration and other chondropathies. In this review, we summarized the advances in the understanding of histone modifications in the regulation of chondrocyte fate, cartilage development and pathology, particularly the molecular writers, erasers and readers involved. In addition, we have highlighted recent studies on the use of small molecules and drugs to manipulate histone signals to regulate chondrocyte functions or treat cartilage lesions, in particular osteoarthritis (OA), and discussed their potential therapeutic benefits and limitations in preventing articular cartilage degeneration or promoting its repair or regeneration.
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Affiliation(s)
- Chao Wan
- MOE Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China.,MOE Key Laboratory for Regenerative Medicine (Shenzhen Base), School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Fengjie Zhang
- MOE Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China.,MOE Key Laboratory for Regenerative Medicine (Shenzhen Base), School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Hanyu Yao
- MOE Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China.,MOE Key Laboratory for Regenerative Medicine (Shenzhen Base), School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Haitao Li
- MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Rocky S Tuan
- MOE Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China.,MOE Key Laboratory for Regenerative Medicine (Shenzhen Base), School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
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Epigenetics and Communication Mechanisms in Microglia Activation with a View on Technological Approaches. Biomolecules 2021; 11:biom11020306. [PMID: 33670563 PMCID: PMC7923060 DOI: 10.3390/biom11020306] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/12/2021] [Accepted: 02/14/2021] [Indexed: 12/13/2022] Open
Abstract
Microglial cells, the immune cells of the central nervous system (CNS), play a crucial role for the proper brain development and function and in CNS homeostasis. While in physiological conditions, microglia continuously check the state of brain parenchyma, in pathological conditions, microglia can show different activated phenotypes: In the early phases, microglia acquire the M2 phenotype, increasing phagocytosis and releasing neurotrophic and neuroprotective factors. In advanced phases, they acquire the M1 phenotype, becoming neurotoxic and contributing to neurodegeneration. Underlying this phenotypic change, there is a switch in the expression of specific microglial genes, in turn modulated by epigenetic changes, such as DNA methylation, histones post-translational modifications and activity of miRNAs. New roles are attributed to microglial cells, including specific communication with neurons, both through direct cell–cell contact and by release of many different molecules, either directly or indirectly, through extracellular vesicles. In this review, recent findings on the bidirectional interaction between neurons and microglia, in both physiological and pathological conditions, are highlighted, with a focus on the complex field of microglia immunomodulation through epigenetic mechanisms and/or released factors. In addition, advanced technologies used to study these mechanisms, such as microfluidic, 3D culture and in vivo imaging, are presented.
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Behera J, Ison J, Rai H, Tyagi N. Allyl sulfide promotes osteoblast differentiation and bone density via reducing mitochondrial DNA release mediated Kdm6b/H3K27me3 epigenetic mechanism. Biochem Biophys Res Commun 2021; 543:87-94. [PMID: 33556823 DOI: 10.1016/j.bbrc.2021.01.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 01/08/2021] [Indexed: 10/22/2022]
Abstract
Age-associated bone loss or osteoporosis is a common clinical manifestation during aging (AG). The mechanism underlying age-associated osteoblast dysfunction induced by oxidative damage in the mitochondria and loss of bone density remains elusive. Here, we demonstrated the effect of allyl sulfide (AS), a natural organosulfur compound, on mitochondrial (mt) function in bone marrow-derived mesenchymal stem cells (BMMSCs) and bone density in AG mice. The data demonstrate that AS treatment in AG mice promotes BMMSCs differentiation and mineralization via inhibition of mitochondrial oxidative damage. The data also indicate that AG related mito-damage was associated with reduced mitochondrial biogenesis and oxidative phosphorylation, and release of a greater concentration of mtDNA. Furthermore, the data showed that mtDNA caused histone H3K27 demethylase inhibition, KDM6B, and subsequent inflammation by unbalancing mitochondrial redox homeostasis. KDM6B overexpression in AG BMMSCs or AS administration in AG mice restores osteogenesis and bone density in vitro and in vivo. Mechanistically, AS or the mitochondrial-specific antioxidant Mito-TEMPO increased KDM6B expression and upregulated the expression of Runx2 in BMMSCs, probably via epigenetic inhibition of H3K27me3 methylation at the promoter. These data uncover the previously undefined role of AS mediated prevention of mtDNA release, promoting osteogenesis and bone density via an epigenetic mechanism. Therefore, AS could be a potential drug target for the treatment of aging-associated osteoporosis.
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Affiliation(s)
- Jyotirmaya Behera
- Bone Biology Laboratory, Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40292, USA
| | - Jessica Ison
- Bone Biology Laboratory, Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40292, USA
| | - Hitesh Rai
- Bone Biology Laboratory, Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40292, USA
| | - Neetu Tyagi
- Bone Biology Laboratory, Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40292, USA.
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Chi YI, Stodola TJ, De Assuncao TM, Leverence EN, Tripathi S, Dsouza NR, Mathison AJ, Basel DG, Volkman BF, Smith BC, Lomberk G, Zimmermann MT, Urrutia R. Molecular mechanics and dynamic simulations of well-known Kabuki syndrome-associated KDM6A variants reveal putative mechanisms of dysfunction. Orphanet J Rare Dis 2021; 16:66. [PMID: 33546721 PMCID: PMC7866879 DOI: 10.1186/s13023-021-01692-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 01/15/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Kabuki syndrome is a genetic disorder that affects several body systems and presents with variations in symptoms and severity. The syndrome is named for a common phenotype of faces resembling stage makeup used in a Japanese traditional theatrical art named kabuki. The most frequent cause of this syndrome is mutations in the H3K4 family of histone methyltransferases while a smaller percentage results from genetic alterations affecting the histone demethylase, KDM6A. Because of the rare presentation of the latter form of the disease, little is known about how missense changes in the KDM6A protein sequence impact protein function. RESULTS In this study, we use molecular mechanic and molecular dynamic simulations to enhance the annotation and mechanistic interpretation of the potential impact of eleven KDM6A missense variants found in Kabuki syndrome patients. These variants (N910S, D980V, S1025G, C1153R, C1153Y, P1195L, L1200F, Q1212R, Q1248R, R1255W, and R1351Q) are predicted to be pathogenic, likely pathogenic or of uncertain significance by sequence-based analysis. Here, we demonstrate, for the first time, that although Kabuki syndrome missense variants are found outside the functionally critical regions, they could affect overall function by significantly disrupting global and local conformation (C1153R, C1153Y, P1195L, L1200F, Q1212R, Q1248R, R1255W and R1351Q), chemical environment (C1153R, C1153Y, P1195L, L1200F, Q1212R, Q1248R, R1255W and R1351Q), and/or molecular dynamics of the catalytic domain (all variants). In addition, our approaches predict that many mutations, in particular C1153R, could allosterically disrupt the key enzymatic interactions of KDM6A. CONCLUSIONS Our study demonstrates that the KDM6A Kabuki syndrome variants may impair histone demethylase function through various mechanisms that include altered protein integrity, local environment, molecular interactions and protein dynamics. Molecular dynamics simulations of the wild type and the variants are critical to gain a better understanding of molecular dysfunction. This type of comprehensive structure- and MD-based analyses should help develop improved impact scoring systems to interpret the damaging effects of variants in this protein and other related proteins as well as provide detailed mechanistic insight that is not currently predictable from sequence alone.
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Affiliation(s)
- Young-In Chi
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.,Bioinformatics Research and Development Laboratory, and Precision Medicine Simulation Unit, GSPMC, Medical College of Wisconsin, Milwaukee, WI, USA.,Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Timothy J Stodola
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.,Bioinformatics Research and Development Laboratory, and Precision Medicine Simulation Unit, GSPMC, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Thiago M De Assuncao
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.,Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Elise N Leverence
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA
| | - Swarnendu Tripathi
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.,Bioinformatics Research and Development Laboratory, and Precision Medicine Simulation Unit, GSPMC, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Nikita R Dsouza
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.,Bioinformatics Research and Development Laboratory, and Precision Medicine Simulation Unit, GSPMC, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Angela J Mathison
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.,Bioinformatics Research and Development Laboratory, and Precision Medicine Simulation Unit, GSPMC, Medical College of Wisconsin, Milwaukee, WI, USA.,Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Donald G Basel
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.,Division of Pediatric Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Brian F Volkman
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Brian C Smith
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Gwen Lomberk
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.,Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.,Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Michael T Zimmermann
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.,Bioinformatics Research and Development Laboratory, and Precision Medicine Simulation Unit, GSPMC, Medical College of Wisconsin, Milwaukee, WI, USA.,Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Raul Urrutia
- Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA. .,Bioinformatics Research and Development Laboratory, and Precision Medicine Simulation Unit, GSPMC, Medical College of Wisconsin, Milwaukee, WI, USA. .,Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA. .,Division of Pediatric Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
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Xu P, Scott DC, Xu B, Yao Y, Feng R, Cheng L, Mayberry K, Wang YD, Bi W, Palmer LE, King MT, Wang H, Li Y, Fan Y, Alpi AF, Li C, Peng J, Papizan J, Pruett-Miller SM, Spallek R, Bassermann F, Cheng Y, Schulman BA, Weiss MJ. FBXO11-mediated proteolysis of BAHD1 relieves PRC2-dependent transcriptional repression in erythropoiesis. Blood 2021; 137:155-167. [PMID: 33156908 PMCID: PMC7820877 DOI: 10.1182/blood.2020007809] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 10/15/2020] [Indexed: 12/15/2022] Open
Abstract
The histone mark H3K27me3 and its reader/writer polycomb repressive complex 2 (PRC2) mediate widespread transcriptional repression in stem and progenitor cells. Mechanisms that regulate this activity are critical for hematopoietic development but are poorly understood. Here we show that the E3 ubiquitin ligase F-box only protein 11 (FBXO11) relieves PRC2-mediated repression during erythroid maturation by targeting its newly identified substrate bromo adjacent homology domain-containing 1 (BAHD1), an H3K27me3 reader that recruits transcriptional corepressors. Erythroblasts lacking FBXO11 are developmentally delayed, with reduced expression of maturation-associated genes, most of which harbor bivalent histone marks at their promoters. In FBXO11-/- erythroblasts, these gene promoters bind BAHD1 and fail to recruit the erythroid transcription factor GATA1. The BAHD1 complex interacts physically with PRC2, and depletion of either component restores FBXO11-deficient erythroid gene expression. Our studies identify BAHD1 as a novel effector of PRC2-mediated repression and reveal how a single E3 ubiquitin ligase eliminates PRC2 repression at many developmentally poised bivalent genes during erythropoiesis.
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Affiliation(s)
| | | | - Beisi Xu
- Department of Computational Biology
| | | | | | | | | | | | | | | | | | - Hong Wang
- Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN
| | - Yuxin Li
- Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN
| | | | - Arno F Alpi
- Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
| | | | - Junmin Peng
- Department of Structural Biology
- Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN
- Department of Development Neurobiology
| | | | - Shondra M Pruett-Miller
- Center for Advanced Genome Engineering, and
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN; and
| | - Ria Spallek
- Department of Medicine III and
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany
| | - Florian Bassermann
- Department of Medicine III and
- TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany
| | - Yong Cheng
- Department of Hematology
- Department of Computational Biology
| | - Brenda A Schulman
- Department of Structural Biology
- Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
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Insa Pineda I, Gómez González CL. The KDM6B mutation: Phenotype and clinical characteristics-Report of a case. REVISTA DE PSIQUIATRIA Y SALUD MENTAL 2021; 15:S1888-9891(21)00001-X. [PMID: 33450416 DOI: 10.1016/j.rpsm.2020.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/19/2020] [Accepted: 12/21/2020] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Alterations in the genes of lysine methylation as Lysine-specific demethylase 6B (KDM6B) have been associated with multiple neurodevelopmental disorders. Until now, there are few cases in the literature attributed to KDM6B mutations. This gap may be due to the fact that the exome sequencing technique is still being implemented in routine clinical practice. MATERIAL AND METHODS A case is presented with its clinical and phenotypic characteristics. The sequence exome analysis was done with the Nimblegen SeqCap EZ MedExome capture kit+mtDNA 47Mb. The psychopathological approach from mental health was carried out through individual and family interviews, the Conner's questionnaires, ADHD rating scale, as well as the psychometry. RESULTS A frameshift variant in the KDM6B gene related to neurodevelopmental disorders with facial and body dysmorphia was obtained. The case was oriented as a neurodevelopmental disorder secondary to a genetic alteration and a comorbid Attention Deficit Hyperactivity Disorder (ADHD). CONCLUSIONS The clinical peculiarities shared by patients identified with the KDM6B mutation, raises the need to recognize it as a particular entity. The possibility of applying the exome sequencing technique to patients with syndromic phenotype and developmental impairment may clarify its etiopathogenesis. It is highly probable that the complexity of these cases requires an approach by a multidisciplinary team that includes genetics, neurology and psychiatry, among other specialties. The coordinated approach is essential to have a comprehensive vision of the case.
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Affiliation(s)
- Inmaculada Insa Pineda
- Child and Adolescent Psychiatry and Psychology, Department of Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain; Children and Adolescent Mental Health Research Group (Consolidated group 2017 SGR 964), Institut de Recerca Sant Joan de Déu, Spain.
| | - Cristina Luz Gómez González
- Child and Adolescent Psychiatry and Psychology, Department of Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
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