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Chen YZ, Zhu XM, Lv P, Hou XK, Pan Y, Li A, Du Z, Xuan JF, Guo X, Xing JX, Liu K, Yao J. Association of histone modification with the development of schizophrenia. Biomed Pharmacother 2024; 175:116747. [PMID: 38744217 DOI: 10.1016/j.biopha.2024.116747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/06/2024] [Accepted: 05/10/2024] [Indexed: 05/16/2024] Open
Abstract
Schizophrenia, influenced by genetic and environmental factors, may involve epigenetic alterations, notably histone modifications, in its pathogenesis. This review summarizes various histone modifications including acetylation, methylation, phosphorylation, ubiquitination, serotonylation, lactylation, palmitoylation, and dopaminylation, and their implications in schizophrenia. Current research predominantly focuses on histone acetylation and methylation, though other modifications also play significant roles. These modifications are crucial in regulating transcription through chromatin remodeling, which is vital for understanding schizophrenia's development. For instance, histone acetylation enhances transcriptional efficiency by loosening chromatin, while increased histone methyltransferase activity on H3K9 and altered histone phosphorylation, which reduces DNA affinity and destabilizes chromatin structure, are significant markers of schizophrenia.
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Affiliation(s)
- Yun-Zhou Chen
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Xiu-Mei Zhu
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Peng Lv
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Xi-Kai Hou
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Ying Pan
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Ang Li
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Zhe Du
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Jin-Feng Xuan
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China
| | - Xiaochong Guo
- Laboratory Animal Center, China Medical University, PR China
| | - Jia-Xin Xing
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China.
| | - Kun Liu
- Key Laboratory of Health Ministry in Congenital Malformation, Shengjing Hospital of China Medical University, PR China.
| | - Jun Yao
- School of Forensic Medicine, China Medical University, PR China; Key Laboratory of Forensic Bio-evidence Sciences, Liaoning Province, PR China; China Medical University Center of Forensic Investigation, PR China.
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Ariyanto EF, Wijaya I, Pradian ZA, Bhaskara APM, Rahman PHA, Oktavia N. Recent Updates on Epigenetic-Based Pharmacotherapy for Atherosclerosis. Diabetes Metab Syndr Obes 2024; 17:1867-1878. [PMID: 38706808 PMCID: PMC11068051 DOI: 10.2147/dmso.s463221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 04/19/2024] [Indexed: 05/07/2024] Open
Abstract
Atherosclerosis is one of the most dominant pathological processes responsible in cardiovascular diseases (CVD) caused by cholesterol accumulation accompanied by inflammation in the arteries which will subsequently lead to further complications, including myocardial infarction and stroke. Although the incidence of atherosclerosis is decreasing in some countries, it is still considered the leading cause of death worldwide. Atherosclerosis is a vascular pathological process that is chronically inflammatory and is characterized by the invasion of inflammatory cells and cytokines. Many reports have unraveled the pivotal roles of epigenetics such as DNA methylation, post-translational histone modifications, and non-coding RNAs (ncRNAs) in atherogenesis, which regulate the expression of numerous genes related to various responsible pathways. Many studies have been conducted to develop new therapeutical approaches based on epigenetic changes for combating atherosclerosis. This review elaborates on recent updates on the development of new atherosclerosis drugs whose mechanism of action is associated with the modulation of DNA methylation, posttranslational histone modifications, and ncRNA-based gene regulation.
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Affiliation(s)
- Eko Fuji Ariyanto
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, Indonesia
| | - Ibnu Wijaya
- Faculty of Medicine, Universitas Padjadjaran, Sumedang, Indonesia
| | | | | | | | - Nandina Oktavia
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Sumedang, Indonesia
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Matsumura Y, Osborne TF, Ito R, Takahashi H, Sakai J. β-Adrenergic Signal and Epigenomic Regulatory Process for Adaptive Thermogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1461:213-227. [PMID: 39289284 DOI: 10.1007/978-981-97-4584-5_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Activation of β-adrenergic (β-AR) signaling induces fight-or-flight stress responses which include enhancement of cardiopulmonary function, metabolic regulation, and muscle contraction. Classical dogma for β-AR signaling has dictated that the receptor-mediated response results in an acute and transient signal. However, more recent studies support more wide-ranging roles for β-AR signaling with long-term effects including cell differentiation that requires precisely timed and coordinated integration of many signaling pathways that culminate in precise epigenomic chromatin modifications. In this chapter, we discuss cold stress/β-AR signaling-induced epigenomic changes in adipose tissues that influence adaptive thermogenesis. We highlight recent studies showing dual roles for the histone demethylase JMJD1A as a mediator of both acute and chronic thermogenic responses to cold stress, in two distinct thermogenic tissues, and through two distinct molecular mechanisms. β-AR signaling not only functions through transient signals during acute stress responses but also relays a more sustained signal to long-term adaptation to environmental changes.
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Affiliation(s)
- Yoshihiro Matsumura
- Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, Akita, Japan
| | - Timothy F Osborne
- Institute for Fundamental Biomedical Research Division of Endocrinology, Diabetes and Metabolism Johns Hopkins University School of Medicine, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA
| | - Ryo Ito
- Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroki Takahashi
- Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Juro Sakai
- Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan.
- Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
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Micale V, Di Bartolomeo M, Di Martino S, Stark T, Dell'Osso B, Drago F, D'Addario C. Are the epigenetic changes predictive of therapeutic efficacy for psychiatric disorders? A translational approach towards novel drug targets. Pharmacol Ther 2023; 241:108279. [PMID: 36103902 DOI: 10.1016/j.pharmthera.2022.108279] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 09/01/2022] [Accepted: 09/01/2022] [Indexed: 02/06/2023]
Abstract
The etiopathogenesis of mental disorders is not fully understood and accumulating evidence support that clinical symptomatology cannot be assigned to a single gene mutation, but it involves several genetic factors. More specifically, a tight association between genes and environmental risk factors, which could be mediated by epigenetic mechanisms, may play a role in the development of mental disorders. Several data suggest that epigenetic modifications such as DNA methylation, post-translational histone modification and interference of microRNA (miRNA) or long non-coding RNA (lncRNA) may modify the severity of the disease and the outcome of the therapy. Indeed, the study of these mechanisms may help to identify patients particularly vulnerable to mental disorders and may have potential utility as biomarkers to facilitate diagnosis and treatment of psychiatric disorders. This article summarizes the most relevant preclinical and human data showing how epigenetic modifications can be central to the therapeutic efficacy of antidepressant and/or antipsychotic agents, as possible predictor of drugs response.
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Affiliation(s)
- Vincenzo Micale
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy.
| | - Martina Di Bartolomeo
- Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Serena Di Martino
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy
| | - Tibor Stark
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Scientific Core Unit Neuroimaging, Max Planck Institute of Psychiatry, Munich, Germany
| | - Bernardo Dell'Osso
- Department of Biomedical and Clinical Sciences 'Luigi Sacco', University of Milan, Milan, Italy, Department of Mental Health, ASST Fatebenefratelli-Sacco, Milan, Italy; "Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan Medical School, Milan, Italy; Department of Psychiatry and Behavioral Sciences, Stanford University, CA, USA
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy.
| | - Claudio D'Addario
- Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Belle R, Kamps JJAG, Poater J, Kumar K, Pieters BJGE, Salah E, Claridge TDW, Paton RS, Bickelhaupt FM, Kawamura A, Schofield CJ, Mecinović J. Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins. Commun Chem 2022; 5:10.1038/s42004-022-00640-4. [PMID: 36071790 PMCID: PMC7613515 DOI: 10.1038/s42004-022-00640-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 02/03/2022] [Indexed: 01/27/2023] Open
Abstract
N ε-Methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription. The 'highest' methylation mark, N ε-trimethyllysine, is specifically recognised by N ε-trimethyllysine binding 'reader' domains, and undergoes demethylation, as catalysed by 2-oxoglutarate dependent JmjC oxygenases. We report studies on the recognition of the closest positively charged N ε-trimethyllysine analogue, i.e. its trimethylphosphonium derivative (KPme3), by N ε-trimethyllysine histone binding proteins and Nε-trimethyllysine demethylases. Calorimetric and computational studies with histone binding proteins reveal that H3KP4me3 binds more tightly than the natural H3K4me3 substrate, though the relative differences in binding affinity vary. Studies with JmjC demethylases show that some, but not all, of them can accept the phosphonium analogue of their natural substrates and that the methylation state selectivity can be changed by substitution of nitrogen for phosphorus. The combined results reveal that very subtle changes, e.g. substitution of nitrogen for phosphorus, can substantially affect interactions between ligand and reader domains / demethylases, knowledge that we hope will inspire the development of highly selective small molecules modulating their activity.
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Affiliation(s)
- Roman Belle
- Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA UK
- Chemistry—School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, NE1 7RU UK
| | - Jos J. A. G. Kamps
- Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA UK
- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
| | - Jordi Poater
- ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain
- Departament de Química Inorgànica i Orgànica & IQTCUB, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain
| | - Kiran Kumar
- Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA UK
| | - Bas J. G. E. Pieters
- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
| | - Eidarus Salah
- Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA UK
| | - Timothy D. W. Claridge
- Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA UK
| | - Robert S. Paton
- Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA UK
| | - F. Matthias Bickelhaupt
- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
- Department of Theoretical Chemistry, Amsterdam Center for Multiscale Modeling, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
| | - Akane Kawamura
- Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA UK
- Chemistry—School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, NE1 7RU UK
| | - Christopher J. Schofield
- Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA UK
| | - Jasmin Mecinović
- Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
- Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark
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Matsumura Y, Osborne TF, Sakai J. Epigenetic and environmental regulation of adipocyte function. J Biochem 2022; 172:9-16. [PMID: 35476139 DOI: 10.1093/jb/mvac033] [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: 02/28/2022] [Accepted: 03/26/2022] [Indexed: 11/14/2022] Open
Abstract
Adipocytes play an essential role in the maintenance of whole-body energy homeostasis. White adipocytes regulate energy storage, whereas brown and beige adipocytes regulate energy expenditure and heat production. De novo production of adipocytes (i.e., adipogenesis) and their functions are dynamically controlled by environmental cues. Environmental changes (e.g., temperature, nutrients, hormones, cytokines) are transmitted via intracellular signaling to facilitate short-term responses and long-term adaptation in adipocytes; however, the molecular mechanisms that link the environment and epigenome are poorly understood. Our recent studies have demonstrated that environmental cues dynamically regulate interactions between transcription factors and epigenomic chromatin regulators, which together trigger combinatorial changes in chromatin structure to influence gene expression in adipocytes. Thus, environmental sensing by the concerted action of multiple chromatin-associated protein complexes is a key determinant of the epigenetic regulation of adipocyte functions.
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Affiliation(s)
- Yoshihiro Matsumura
- Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan
| | - Timothy F Osborne
- Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, and Medicine in the Division of Endocrinology, Diabetes and Metabolism of the Johns Hopkins University School of Medicine, Petersburg, FL, USA
| | - Juro Sakai
- Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.,Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
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Rudzki S. Is PTSD an Evolutionary Survival Adaptation Initiated by Unrestrained Cytokine Signaling and Maintained by Epigenetic Change? Mil Med 2022; 188:usac095. [PMID: 35446412 DOI: 10.1093/milmed/usac095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/01/2022] [Accepted: 03/24/2022] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Treatment outcomes for PTSD with current psychological therapies are poor, with very few patients achieving sustained symptom remission. A number of authors have identified physiological and immune disturbances in Post Traumatic Stress Disorder (PTSD) patients, but there is no unifying hypothesis that explains the myriad features of the disorder. MATERIALS AND METHODS The medical literature was reviewed over a 6-year period primarily using the medical database PUBMED. RESULTS The literature contains numerous papers that have identified a range of physiological and immune dysfunction in association with PTSD. This paper proposes that unrestrained cytokine signaling induces epigenetic changes that promote an evolutionary survival adaptation, which maintains a defensive PTSD phenotype. The brain can associate immune signaling with past threat and initiate a defensive behavioral response. The sympathetic nervous system is pro-inflammatory, while the parasympathetic nervous system is anti-inflammatory. Prolonged cholinergic withdrawal will promote a chronic inflammatory state. The innate immune cytokine IL-1β has pleiotropic properties and can regulate autonomic, glucocorticoid, and glutamate receptor functions, sleep, memory, and epigenetic enzymes. Changes in epigenetic enzyme activity can potentially alter phenotype and induce an adaptation. Levels of IL-1β correlate with severity and duration of PTSD and PTSD can be prevented by bolus administration of hydrocortisone in acute sepsis, consistent with unrestrained inflammation being a risk factor for PTSD. The nervous and immune systems engage in crosstalk, governed by common receptors. The benefits of currently used psychiatric medication may arise from immune, as well as synaptic, modulation. The psychedelic drugs (3,4-Methylenedioxymethamphetamine (MDMA), psilocybin, and ketamine) have potent immunosuppressive and anti-inflammatory effects on the adaptive immune system, which may contribute to their reported benefit in PTSD. There may be distinct PTSD phenotypes induced by innate and adaptive cytokine signaling. CONCLUSION In order for an organism to survive, it must adapt to its environment. Cytokines signal danger to the brain and can induce epigenetic changes that result in a persistent defensive phenotype. PTSD may be the price individuals pay for the genomic flexibility that promotes adaptation and survival.
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Affiliation(s)
- Stephan Rudzki
- Canberra Sports Medicine, Deakin, Australian Capital Territory 2600, Australia
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Pokrovsky D, Forné I, Straub T, Imhof A, Rupp RAW. A systemic cell cycle block impacts stage-specific histone modification profiles during Xenopus embryogenesis. PLoS Biol 2021; 19:e3001377. [PMID: 34491983 PMCID: PMC8535184 DOI: 10.1371/journal.pbio.3001377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/22/2021] [Accepted: 07/30/2021] [Indexed: 11/26/2022] Open
Abstract
Forming an embryo from a zygote poses an apparent conflict for epigenetic regulation. On the one hand, the de novo induction of cell fate identities requires the establishment and subsequent maintenance of epigenetic information to harness developmental gene expression. On the other hand, the embryo depends on cell proliferation, and every round of DNA replication dilutes preexisting histone modifications by incorporation of new unmodified histones into chromatin. Here, we investigated the possible relationship between the propagation of epigenetic information and the developmental cell proliferation during Xenopus embryogenesis. We systemically inhibited cell proliferation during the G1/S transition in gastrula embryos and followed their development until the tadpole stage. Comparing wild-type and cell cycle-arrested embryos, we show that the inhibition of cell proliferation is principally compatible with embryo survival and cellular differentiation. In parallel, we quantified by mass spectrometry the abundance of a large set of histone modification states, which reflects the developmental maturation of the embryonic epigenome. The arrested embryos developed abnormal stage-specific histone modification profiles (HMPs), in which transcriptionally repressive histone marks were overrepresented. Embryos released from the cell cycle block during neurulation reverted toward normality on morphological, molecular, and epigenetic levels. These results suggest that the cell cycle block by HUA alters stage-specific HMPs. We propose that this influence is strong enough to control developmental decisions, specifically in cell populations that switch between resting and proliferating states such as stem cells.
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Affiliation(s)
- Daniil Pokrovsky
- Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Ignasi Forné
- Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Tobias Straub
- Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Axel Imhof
- Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Ralph A. W. Rupp
- Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
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Denzer L, Schroten H, Schwerk C. From Gene to Protein-How Bacterial Virulence Factors Manipulate Host Gene Expression During Infection. Int J Mol Sci 2020; 21:ijms21103730. [PMID: 32466312 PMCID: PMC7279228 DOI: 10.3390/ijms21103730] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/19/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023] Open
Abstract
Bacteria evolved many strategies to survive and persist within host cells. Secretion of bacterial effectors enables bacteria not only to enter the host cell but also to manipulate host gene expression to circumvent clearance by the host immune response. Some effectors were also shown to evade the nucleus to manipulate epigenetic processes as well as transcription and mRNA procession and are therefore classified as nucleomodulins. Others were shown to interfere downstream with gene expression at the level of mRNA stability, favoring either mRNA stabilization or mRNA degradation, translation or protein stability, including mechanisms of protein activation and degradation. Finally, manipulation of innate immune signaling and nutrient supply creates a replicative niche that enables bacterial intracellular persistence and survival. In this review, we want to highlight the divergent strategies applied by intracellular bacteria to evade host immune responses through subversion of host gene expression via bacterial effectors. Since these virulence proteins mimic host cell enzymes or own novel enzymatic functions, characterizing their properties could help to understand the complex interactions between host and pathogen during infections. Additionally, these insights could propose potential targets for medical therapy.
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Analysis of Heterodimeric "Mutual Synergistic Folding"-Complexes. Int J Mol Sci 2019; 20:ijms20205136. [PMID: 31623284 PMCID: PMC6829572 DOI: 10.3390/ijms20205136] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/07/2019] [Accepted: 10/15/2019] [Indexed: 12/17/2022] Open
Abstract
Several intrinsically disordered proteins (IDPs) are capable to adopt stable structures without interacting with a folded partner. When the folding of all interacting partners happens at the same time, coupled with the interaction in a synergistic manner, the process is called Mutual Synergistic Folding (MSF). These complexes represent a discrete subset of IDPs. Recently, we collected information on their complexes and created the MFIB (Mutual Folding Induced by Binding) database. In a previous study, we compared homodimeric MSF complexes with homodimeric and monomeric globular proteins with similar amino acid sequence lengths. We concluded that MSF homodimers, compared to globular homodimeric proteins, have a greater solvent accessible main-chain surface area on the contact surface of the subunits, which becomes buried during dimerization. The main driving force of the folding is the mutual shielding of the water-accessible backbones, but the formation of further intermolecular interactions can also be relevant. In this paper, we will report analyses of heterodimeric MSF complexes. Our results indicate that the amino acid composition of the heterodimeric MSF monomer subunits slightly diverges from globular monomer proteins, while after dimerization, the amino acid composition of the overall MSF complexes becomes more similar to overall amino acid compositions of globular complexes. We found that inter-subunit interactions are strengthened, and additionally to the shielding of the solvent accessible backbone, other factors might play an important role in the stabilization of the heterodimeric structures, likewise energy gain resulting from the interaction of the two subunits with different amino acid compositions. We suggest that the shielding of the β-sheet backbones and the formation of a buried structural core along with the general strengthening of inter-subunit interactions together could be the driving forces of MSF protein structural ordering upon dimerization.
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Arora I, Sharma M, Tollefsbol TO. Combinatorial Epigenetics Impact of Polyphenols and Phytochemicals in Cancer Prevention and Therapy. Int J Mol Sci 2019; 20:ijms20184567. [PMID: 31540128 PMCID: PMC6769666 DOI: 10.3390/ijms20184567] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/08/2019] [Accepted: 09/11/2019] [Indexed: 12/24/2022] Open
Abstract
Polyphenols are potent micronutrients that can be found in large quantities in various food sources and spices. These compounds, also known as phenolics due to their phenolic structure, play a vital nutrient-based role in the prevention of various diseases such as diabetes, cardiovascular diseases, neurodegenerative diseases, liver disease, and cancers. However, the function of polyphenols in disease prevention and therapy depends on their dietary consumption and biological properties. According to American Cancer Society statistics, there will be an expected rise of 23.6 million new cancer cases by 2030. Due to the severity of the increased risk, it is important to evaluate various preventive measures associated with cancer. Relatively recently, numerous studies have indicated that various dietary polyphenols and phytochemicals possess properties of modifying epigenetic mechanisms that modulate gene expression resulting in regulation of cancer. These polyphenols and phytochemicals, when administrated in a dose-dependent and combinatorial-based manner, can have an enhanced effect on epigenetic changes, which play a crucial role in cancer prevention and therapy. Hence, this review will focus on the mechanisms of combined polyphenols and phytochemicals that can impact various epigenetic modifications such as DNA methylation and histone modifications as well as regulation of non-coding miRNAs expression for treatment and prevention of various types of cancer.
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Affiliation(s)
- Itika Arora
- Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Birmingham, AL 35294, USA.
| | - Manvi Sharma
- Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Birmingham, AL 35294, USA.
| | - Trygve O Tollefsbol
- Department of Biology, University of Alabama at Birmingham, 1300 University Boulevard, Birmingham, AL 35294, USA.
- Comprehensive Center for Healthy Aging, University of Alabama Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294, USA.
- Comprehensive Cancer Center, University of Alabama Birmingham, 1802 6th Avenue South, Birmingham, AL 35294, USA.
- Nutrition Obesity Research Center, University of Alabama Birmingham, 1675 University Boulevard, Birmingham, AL 35294, USA.
- Comprehensive Diabetes Center, University of Alabama Birmingham, 1825 University Boulevard, Birmingham, AL 35294, USA.
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Chromatin dynamics underlying the precise regeneration of a vertebrate limb - Epigenetic regulation and cellular memory. Semin Cell Dev Biol 2019; 97:16-25. [PMID: 30991117 DOI: 10.1016/j.semcdb.2019.04.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 04/01/2019] [Accepted: 04/09/2019] [Indexed: 12/13/2022]
Abstract
Wound healing, tissue regeneration, and organ regrowth are all regeneration phenomena observed in vertebrates after an injury. However, the ability to regenerate differs greatly among species. Mammals can undergo wound healing and tissue regeneration, but cannot regenerate an organ; for example, they cannot regrow an amputated limb. In contrast, amphibians and fish have much higher capabilities for organ-level regeneration. In addition to medical studies and those in conventional mammalian models such as mice, studies in amphibians and fish have revealed essential factors for and mechanisms of regeneration, including the regrowth of a limb, tail, or fin. However, the molecular nature of the cellular memory needed to precisely generate a new appendage from an amputation site is not fully understood. Recent reports have indicated that organ regeneration is closely related to epigenetic regulation. For example, the methylation status of genomic DNA is related to the expression of regeneration-related genes, and histone-modification enzymes are required to control the chromatin dynamics for regeneration. A proposed mechanism of cellular memory involving an inheritable system of epigenetic modification led us to hypothesize that epigenetic regulation forms the basis for cellular memory in organ regeneration. Here we summarize the current understanding of the role of epigenetic regulation in organ regeneration and discuss the relationship between organ regeneration and epigenetic memory.
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Sang Y, Sun L, Wu Y, Yuan W, Liu Y, Li SW. Histone deacetylase 7 inhibits plakoglobin expression to promote lung cancer cell growth and metastasis. Int J Oncol 2019; 54:1112-1122. [PMID: 30628670 DOI: 10.3892/ijo.2019.4682] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 12/06/2018] [Indexed: 11/05/2022] Open
Abstract
Plakoglobin is a tumor suppressor gene in lung cancer; however, the mechanism by which it is downregulated in lung cancer is largely unknown. The aim of the present study was to investigate whether histone deacetylases (HDACs) regulate plakoglobin expression in lung cancer. The effects of overexpression or knockdown of HDAC7 on plakoglobin were determined using stably transfected lung cancer cell lines. Chromatin immunoprecipitation assays were performed to elucidate the mechanisms underlying the HDAC7‑induced suppression of plakoglobin. A Cell Counting Kit‑8 and Transwell assays were performed, and a nude mouse in vivo model was established to investigate the role of the HDAC7/plakoglobin pathway in cell migration, invasion and metastasis. Ectopic expression of HDAC7 was identified to suppress mRNA and protein levels of plakoglobin in lung cancer cells, whereas silencing HDAC7 with short hairpin RNA increased the expression of plakoglobin. HDAC7 was proposed to suppressed plakoglobin by directly binding to its promoter. Overexpression or knockdown of HDAC7 promoted or inhibited cell proliferation, migration and invasion, respectively. Furthermore, knockdown of HDAC7 significantly suppressed tumor growth and metastasis in vivo. In addition, overexpression of plakoglobin significantly reduced the enhanced cell proliferation, migration and invasion induced by ectopic HDAC7. In conclusion, suppression of plakoglobin by HDAC7 promoted the proliferation, migration, invasion and metastasis in lung cancer. This novel axis of HDAC7/plakoglobin may be valuable in the development of novel therapeutic strategies for treating patients with lung cancer.
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Affiliation(s)
- Yi Sang
- Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, Department of Center Laboratory, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Longhua Sun
- Department of Respiratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Yuanzhong Wu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Wenxin Yuan
- Department of Ultrasonography, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Yanyan Liu
- Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Si-Wei Li
- Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, Hubei 430079, P.R. China
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Ershov NI, Bondar NP, Lepeshko AA, Reshetnikov VV, Ryabushkina JA, Merkulova TI. Consequences of early life stress on genomic landscape of H3K4me3 in prefrontal cortex of adult mice. BMC Genomics 2018; 19:93. [PMID: 29504911 PMCID: PMC5836825 DOI: 10.1186/s12864-018-4479-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Maternal separation models in rodents are widely used to establish molecular mechanisms underlying prolonged effects of early life adversity on neurobiological and behavioral outcomes in adulthood. However, global epigenetic signatures following early life stress in these models remain unclear. Results In this study, we carried out a ChIP-seq analysis of H3K4 trimethylation profile in the prefrontal cortex of adult male mice with a history of early life stress. Two types of stress were used: prolonged separation of pups from their mothers (for 3 h once a day, maternal separation, MS) and brief separation (for 15 min once a day, handling, HD). Adult offspring in the MS group demonstrated reduced locomotor activity in the open field test accompanied by reduced exploratory activity, while the HD group showed decreased anxiety-like behavior only. In a group of maternal separation, we have found a small number (45) of slightly up-regulated peaks, corresponding to promoters of 70 genes, while no changes were observed in a group of handling. Among the genes whose promoters have differential enrichment of H3K4me3, the most relevant ones participate in gene expression regulation, modulation of chromatin structure and mRNA processing. For two genes, Ddias and Pip4k2a, increased H3K4me3 levels were associated with the increased mRNA expression in MS group. Conclusion The distribution of H3K4me3 in prefrontal cortex showed relatively low variability across all individuals, and only some subtle changes were revealed in mice with a history of early life stress. It is possible that the observed long-lasting behavioral alterations induced by maternal separation are mediated by other epigenetic mechanisms, or other brain structures are responsible for these effects. Electronic supplementary material The online version of this article (10.1186/s12864-018-4479-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Nikita I Ershov
- Laboratory of Gene Expression Regulation, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 10 Prospect Lavrentyeva, 630090, Novosibirsk, Russia
| | - Natalya P Bondar
- Laboratory of Gene Expression Regulation, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 10 Prospect Lavrentyeva, 630090, Novosibirsk, Russia. .,Novosibirsk National Research State University, 2 Pirogov Street, 630090, Novosibirsk, Russia.
| | - Arina A Lepeshko
- Laboratory of Gene Expression Regulation, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 10 Prospect Lavrentyeva, 630090, Novosibirsk, Russia.,Novosibirsk National Research State University, 2 Pirogov Street, 630090, Novosibirsk, Russia
| | - Vasiliy V Reshetnikov
- Laboratory of Gene Expression Regulation, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 10 Prospect Lavrentyeva, 630090, Novosibirsk, Russia
| | - Julia A Ryabushkina
- Novosibirsk National Research State University, 2 Pirogov Street, 630090, Novosibirsk, Russia
| | - Tatiana I Merkulova
- Laboratory of Gene Expression Regulation, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 10 Prospect Lavrentyeva, 630090, Novosibirsk, Russia.,Novosibirsk National Research State University, 2 Pirogov Street, 630090, Novosibirsk, Russia
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Lee S, Lee J, Chae S, Moon Y, Lee HY, Park B, Yang EG, Hwang D, Park H. Multi-dimensional histone methylations for coordinated regulation of gene expression under hypoxia. Nucleic Acids Res 2017; 45:11643-11657. [PMID: 28977425 PMCID: PMC5714201 DOI: 10.1093/nar/gkx747] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Accepted: 08/22/2017] [Indexed: 02/06/2023] Open
Abstract
Hypoxia increases both active and repressive histone methylation levels via decreased activity of histone demethylases. However, how such increases coordinately regulate induction or repression of hypoxia-responsive genes is largely unknown. Here, we profiled active and repressive histone tri-methylations (H3K4me3, H3K9me3, and H3K27me3) and analyzed gene expression profiles in human adipocyte-derived stem cells under hypoxia. We identified differentially expressed genes (DEGs) and differentially methylated genes (DMGs) by hypoxia and clustered the DEGs and DMGs into four major groups. We found that each group of DEGs was predominantly associated with alterations in only one type among the three histone tri-methylations. Moreover, the four groups of DEGs were associated with different TFs and localization patterns of their predominant types of H3K4me3, H3K9me3 and H3K27me3. Our results suggest that the association of altered gene expression with prominent single-type histone tri-methylations characterized by different localization patterns and with different sets of TFs contributes to regulation of particular sets of genes, which can serve as a model for coordinated epigenetic regulation of gene expression under hypoxia.
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Affiliation(s)
- Seongyeol Lee
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
| | - Jieon Lee
- Department of Chemical Engineering, POSTECH, Pohang 37673, Republic of Korea
| | - Sehyun Chae
- Department of New Biology and Center for Plant Aging Research, Institute of Basic Science, DGIST, Daegu 42988, Republic of Korea
| | - Yunwon Moon
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
| | - Ho-Youl Lee
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
| | - Bongju Park
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
| | - Eun Gyeong Yang
- Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Daehee Hwang
- Department of Chemical Engineering, POSTECH, Pohang 37673, Republic of Korea.,Department of New Biology and Center for Plant Aging Research, Institute of Basic Science, DGIST, Daegu 42988, Republic of Korea
| | - Hyunsung Park
- Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea
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Role of influenza A virus NP acetylation on viral growth and replication. Nat Commun 2017; 8:1259. [PMID: 29097654 PMCID: PMC5668263 DOI: 10.1038/s41467-017-01112-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 08/17/2017] [Indexed: 12/29/2022] Open
Abstract
Lysine acetylation is a post-translational modification known to regulate protein functions. Here we identify several acetylation sites of the influenza A virus nucleoprotein (NP), including the lysine residues K77, K113 and K229. Viral growth of mutant virus encoding K229R, mimicking a non-acetylated NP lysine residue, is severely impaired compared to wildtype or the mutant viruses encoding K77R or K113R. This attenuation is not the result of decreased polymerase activity, altered protein expression or disordered vRNP co-segregation but rather caused by impaired particle release. Interestingly, release deficiency is also observed mimicking constant acetylation at this site (K229Q), whereas virus encoding NP-K113Q could not be generated. However, mimicking NP hyper-acetylation at K77 and K229 severely diminishes viral polymerase activity, while mimicking NP hypo-acetylation at these sites has no effect on viral replication. These results suggest that NP acetylation at K77, K113 and K229 impacts multiple steps in viral replication of influenza A viruses. Post-translational modifications of influenza A virus proteins can regulate virus replication, but the effect of nucleoprotein (NP) acetylation is not known. Here, Giese et al. identify four NP lysine residues that are acetylated in infected cells and study their role in polymerase activity and virion release.
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17
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Dong X, Wang X, Zhang F, Tian W. Genome-Wide Identification of Regulatory Sequences Undergoing Accelerated Evolution in the Human Genome. Mol Biol Evol 2016; 33:2565-75. [PMID: 27401230 PMCID: PMC5026254 DOI: 10.1093/molbev/msw128] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Accelerated evolution of regulatory sequence can alter the expression pattern of target genes, and cause phenotypic changes. In this study, we used DNase I hypersensitive sites (DHSs) to annotate putative regulatory sequences in the human genome, and conducted a genome-wide analysis of the effects of accelerated evolution on regulatory sequences. Working under the assumption that local ancient repeat elements of DHSs are under neutral evolution, we discovered that ∼0.44% of DHSs are under accelerated evolution (ace-DHSs). We found that ace-DHSs tend to be more active than background DHSs, and are strongly associated with epigenetic marks of active transcription. The target genes of ace-DHSs are significantly enriched in neuron-related functions, and their expression levels are positively selected in the human brain. Thus, these lines of evidences strongly suggest that accelerated evolution on regulatory sequences plays important role in the evolution of human-specific phenotypes.
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Affiliation(s)
- Xinran Dong
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Biostatistics and Computational Biology, School of Life Sciences, Fudan University, Shanghai, P.R. China
| | - Xiao Wang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Biostatistics and Computational Biology, School of Life Sciences, Fudan University, Shanghai, P.R. China
| | - Feng Zhang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Biostatistics and Computational Biology, School of Life Sciences, Fudan University, Shanghai, P.R. China
| | - Weidong Tian
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Biostatistics and Computational Biology, School of Life Sciences, Fudan University, Shanghai, P.R. China Children's Hospital of Fudan University, Shanghai, P.R. China
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18
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Kim HY, Wegner SH, Van Ness KP, Park JJ, Pacheco SE, Workman T, Hong S, Griffith W, Faustman EM. Differential epigenetic effects of chlorpyrifos and arsenic in proliferating and differentiating human neural progenitor cells. Reprod Toxicol 2016; 65:212-223. [PMID: 27523287 DOI: 10.1016/j.reprotox.2016.08.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 07/21/2016] [Accepted: 08/10/2016] [Indexed: 12/16/2022]
Abstract
Understanding the underlying temporal and mechanistic responses to neurotoxicant exposures during sensitive periods of neuronal development are critical for assessing the impact of these exposures on developmental processes. To investigate the importance of timing of neurotoxicant exposure for perturbation of epigenetic regulation, we exposed human neuronal progenitor cells (hNPCs) to chlorpyrifos (CP) and sodium arsenite (As; positive control) during proliferation and differentiation. CP or As treatment effects on hNPCs morphology, cell viability, and changes in protein expression levels of neural differentiation and cell stress markers, and histone H3 modifications were examined. Cell viability, proliferation/differentiation status, and epigenetic results suggest that hNPCs cultures respond to CP and As treatment with different degrees of sensitivity. Histone modifications, as measured by changes in histone H3 phosphorylation, acetylation and methylation, varied for each toxicant and growth condition, suggesting that differentiation status can influence the epigenetic effects of CP and As exposures.
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Affiliation(s)
- Hee Yeon Kim
- Department of Environmental and Occupational Health, Institute of Risk Analysis and Risk Communication, University of Washington, 4225 Roosevelt Way NE, Seattle, WA, United States
| | - Susanna H Wegner
- Department of Environmental and Occupational Health, Institute of Risk Analysis and Risk Communication, University of Washington, 4225 Roosevelt Way NE, Seattle, WA, United States
| | - Kirk P Van Ness
- Department of Environmental and Occupational Health, Institute of Risk Analysis and Risk Communication, University of Washington, 4225 Roosevelt Way NE, Seattle, WA, United States
| | - Julie Juyoung Park
- Department of Environmental and Occupational Health, Institute of Risk Analysis and Risk Communication, University of Washington, 4225 Roosevelt Way NE, Seattle, WA, United States
| | - Sara E Pacheco
- Department of Environmental and Occupational Health, Institute of Risk Analysis and Risk Communication, University of Washington, 4225 Roosevelt Way NE, Seattle, WA, United States
| | - Tomomi Workman
- Department of Environmental and Occupational Health, Institute of Risk Analysis and Risk Communication, University of Washington, 4225 Roosevelt Way NE, Seattle, WA, United States
| | - Sungwoo Hong
- Department of Environmental and Occupational Health, Institute of Risk Analysis and Risk Communication, University of Washington, 4225 Roosevelt Way NE, Seattle, WA, United States
| | - William Griffith
- Department of Environmental and Occupational Health, Institute of Risk Analysis and Risk Communication, University of Washington, 4225 Roosevelt Way NE, Seattle, WA, United States
| | - Elaine M Faustman
- Department of Environmental and Occupational Health, Institute of Risk Analysis and Risk Communication, University of Washington, 4225 Roosevelt Way NE, Seattle, WA, United States.
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19
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Matsumura Y, Nakaki R, Inagaki T, Yoshida A, Kano Y, Kimura H, Tanaka T, Tsutsumi S, Nakao M, Doi T, Fukami K, Osborne TF, Kodama T, Aburatani H, Sakai J. H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipocyte Differentiation. Mol Cell 2016; 60:584-96. [PMID: 26590716 DOI: 10.1016/j.molcel.2015.10.025] [Citation(s) in RCA: 159] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 08/11/2015] [Accepted: 10/12/2015] [Indexed: 12/29/2022]
Abstract
Bivalent H3K4me3 and H3K27me3 chromatin domains in embryonic stem cells keep active developmental regulatory genes expressed at very low levels and poised for activation. Here, we show an alternative and previously unknown bivalent modified histone signature in lineage-committed mesenchymal stem cells and preadipocytes that pairs H3K4me3 with H3K9me3 to maintain adipogenic master regulatory genes (Cebpa and Pparg) expressed at low levels yet poised for activation when differentiation is required. We show lineage-specific gene-body DNA methylation recruits H3K9 methyltransferase SETDB1, which methylates H3K9 immediately downstream of transcription start sites marked with H3K4me3 to establish the bivalent domain. At the Cebpa locus, this prevents transcription factor C/EBPβ binding, histone acetylation, and further H3K4me3 deposition and is associated with pausing of RNA polymerase II, which limits Cebpa gene expression and adipogenesis.
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Affiliation(s)
- Yoshihiro Matsumura
- Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
| | - Ryo Nakaki
- Genome Science Division, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan
| | - Takeshi Inagaki
- Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Ayano Yoshida
- Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan
| | - Yuka Kano
- Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan
| | - Hiroshi Kimura
- Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan
| | - Toshiya Tanaka
- Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Shuichi Tsutsumi
- Genome Science Division, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan
| | - Mitsuyoshi Nakao
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
| | - Takefumi Doi
- Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan
| | - Kiyoko Fukami
- Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan
| | - Timothy F Osborne
- Metabolic Disease Program, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA
| | - Tatsuhiko Kodama
- Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan
| | - Hiroyuki Aburatani
- Genome Science Division, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Juro Sakai
- Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
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20
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Georgel PT. The danger of epigenetics misconceptions (epigenetics and stuff…). Biochem Cell Biol 2015; 93:626-9. [DOI: 10.1139/bcb-2015-0091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Within the past two decades, the fields of chromatin structure and function and transcription regulation research started to fuse and overlap, as evidence mounted to support a very strong regulatory role in gene expression that was associated with histone post-translational modifications, DNA methylation, as well as various chromatin-associated proteins (the pillars of the “Epigenetics” building). The fusion and convergence of these complementary fields is now often simply referred to as “Epigenetics”. During these same 20 years, numerous new research groups have started to recognize the importance of chromatin composition, conformation, and its plasticity. However, as the field started to grow exponentially, its growth came with the spreading of several important misconceptions, which have unfortunately led to improper or hasty conclusions. The goal of this short “opinion” piece is to attempt to minimize future misinterpretations of experimental results and ensure that the right sets of experiment are used to reach the proper conclusion, at least as far as epigenetic mechanisms are concerned.
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Affiliation(s)
- Philippe T. Georgel
- Department of Biological Sciences, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA
- Cell Differentiation and Development Center, Marshall University, Huntington, WV 25755, USA
- Department of Biochemistry and Microbiology, Marshall University School of Medicine, Huntington, WV 25755, USA
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Ueno A, Ghosh A, Hung D, Li J, Jijon H. Th17 plasticity and its changes associated with inflammatory bowel disease. World J Gastroenterol 2015; 21:12283-95. [PMID: 26604637 PMCID: PMC4649113 DOI: 10.3748/wjg.v21.i43.12283] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 08/17/2015] [Accepted: 10/23/2015] [Indexed: 02/06/2023] Open
Abstract
CD4 T helper (Th) cell differentiation into distinct T cell subsets is critical to the normal function of the immune system. Until recently, the paradigm held that naïve T cells differentiated into distinct subsets under the guidance of environmental cues (e.g., cytokines) and that once polarized, these cells were committed to a particular functional state. However, the existence of transdifferentiated T cell populations, which express signature transcription factors and cytokines associated with more than one Th subset, challenges the immutability of T helper subsets and suggests that plasticity is a feature of multifaceted immune responses. How this process impacts immune dysregulation in diseases such as inflammatory bowel diseases (IBD) and the machinery that underlies this process is far from fully understood. Interleukin (IL)-17 secreting helper T (Th17) cells have been heavily implicated in tissue-specific immune pathology including murine models of IBD, human Crohn's disease and ulcerative colitis. Plasticity within this subset is suggested by the existence of IL-17 secreting cells, which, can also secrete interferon-γ, the signature cytokine for Th1 cells or, can co-express the anti-inflammatory transcription factor forkhead box p3, a signature transcription factor of regulatory T cells. In this review we mainly discuss evidence for Th17 plasticity, mechanisms, which govern it, and highlight the potential to therapeutically target this process in human IBD.
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22
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Donnenberg VS, Donnenberg AD. Stem cell state and the epithelial-to-mesenchymal transition: Implications for cancer therapy. J Clin Pharmacol 2015; 55:603-19. [PMID: 25708160 DOI: 10.1002/jcph.486] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 02/19/2015] [Indexed: 01/09/2023]
Abstract
The cancer stem cell paradigm, the epithelial-to-mesenchymal transition and its converse, the mesenchymal-to-epithelial transition, have reached convergence. Implicit in this understanding is the notion that cancer cells can change state, and with such change come bidirectional alterations in motility, proliferative activity, and drug resistance. As such, tumors present a moving target for antineoplastic therapy. This article will review the evolving adult stem cell paradigm and how changes in our understanding of the bidirectional nature of cancer cell differentiation may affect the selection and timing of antineoplastic therapy. The goal is to determine how to best administer therapies potentially targeted against the cancer stem cell state in the context of established treatment regimens, and to evaluate long-term effects beyond tumor regression.
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Affiliation(s)
- Vera S Donnenberg
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
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Vriet C, Hennig L, Laloi C. Stress-induced chromatin changes in plants: of memories, metabolites and crop improvement. Cell Mol Life Sci 2015; 72:1261-73. [PMID: 25578097 PMCID: PMC11113909 DOI: 10.1007/s00018-014-1792-z] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Revised: 11/19/2014] [Accepted: 11/20/2014] [Indexed: 01/18/2023]
Abstract
Exposure of plants to adverse environmental conditions leads to extensive transcriptional changes. Genome-wide approaches and gene function studies have revealed the importance of chromatin-level control in the regulation of stress-responsive gene expression. Advances in understanding chromatin modifications implicated in plant stress response and identifying proteins involved in chromatin-mediated transcriptional responses to stress are briefly presented in this review. We then highlight how chromatin-mediated gene expression changes can be coupled to the metabolic status of the cell, since many of the chromatin-modifying proteins involved in transcriptional regulation depend on cofactors and metabolites that are shared with enzymes in basic metabolism. Lastly, we discuss the stability and heritability of stress-induced chromatin changes and the potential of chromatin-based strategies for increasing stress tolerance of crops.
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Affiliation(s)
- Cécile Vriet
- BVME UMR 7265, Lab Genet Biophys Plantes, Aix Marseille Université, Marseille, 13284, France,
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Low activity of LSD1 elicits a pro-inflammatory gene expression profile in riboflavin-deficient human T Lymphoma Jurkat cells. GENES AND NUTRITION 2014; 9:422. [PMID: 25103574 DOI: 10.1007/s12263-014-0422-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 07/25/2014] [Indexed: 02/07/2023]
Abstract
Mono- and dimethylation of lysine (K)-4 in histone H3 (H3K4me1, H3K4me2) create epigenetic gene activation marks that are enriched near the transcription start site of genes. Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD)-dependent demethylase that catalyzes the demethylation of H3K4me1 and H3K4me2, thereby mediating gene repression. This study tested the hypothesis that LSD1 activity depends on the concentrations of the FAD precursor, riboflavin, in cell culture media, and that riboflavin deficiency causes derepression of pro-inflammatory cytokines. Human T lymphoma Jurkat cells were cultured in riboflavin-defined media, representing plasma levels of riboflavin in moderately deficient, sufficient, and supplemented humans. The expression of LSD1 mRNA and protein followed the pattern riboflavin-deficient > riboflavin-sufficient > riboflavin-supplemented cells. However, the increase in LSD1 expression was insufficient to compensate for FAD depletion, and LSD activities were more than 30 % higher in riboflavin-supplemented cells compared with the other treatment groups. The enrichment of H3K4me2 marks was 11-137 % greater in riboflavin-deficient cells compared with sufficient cells in exon 1 of genes coding for the pro-inflammatory cytokines interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor-α. Consistent with the enrichment of gene activation marks, the expression of mRNA coding for pro-inflammatory cytokines was 62-487 % higher in riboflavin-deficient cells compared with sufficient cells. These findings support the hypothesis that riboflavin deficiency contributes toward a pro-inflammatory gene expression pattern through a loss of LSD1 activity.
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Roidl D, Hacker C. Histone methylation during neural development. Cell Tissue Res 2014; 356:539-52. [PMID: 24817100 DOI: 10.1007/s00441-014-1842-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 02/03/2014] [Indexed: 12/15/2022]
Abstract
Post-translational modification of histone proteins, such as the methylation of lysine and arginine residues, influences the higher order of chromatin and leads to gene activation or silencing. Histone methyltransferases or demethylases actively add or remove various methylation marks in a cell-type-specific and context-dependent way. They are therefore important players in regulating the transcriptional program of a cell. Some control of the various cellular programs is necessary during the differentiation of stem cells along a specific lineage, when differentiation to alternative lineages needs to be suppressed. One example is the development of neurons from neural stem cells during neurogenesis. Neurogenesis is a highly organized process that requires the proper coordination of survival, proliferation, differentiation and migration signals. This holds true for both embryonic and neural stem cells that give rise to the various cell types of the central nervous system. The control of embryonic and neural stem cell self-renewal and differentiation is achieved by both extrinsic and intrinsic signals that regulate gene expression precisely. Recent advances in neuroscience support the importance of epigenetic modifications, such as the methylation and acetylation of histones, as an important intrinsic mechanism for the regulation of central nervous system development. This review summarizes our current knowledge of histone methylation processes during neural development and provides insights into the function of histone methylation enzymes and their role during central nervous system development.
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Affiliation(s)
- Deborah Roidl
- Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany
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Zhu JJ, Kam MK, Garcia-Barceló MM, Tam PKH, Lui VCH. HOXB5 binds to multi-species conserved sequence (MCS+9.7) of RET gene and regulates RET expression. Int J Biochem Cell Biol 2014; 51:142-9. [PMID: 24794774 DOI: 10.1016/j.biocel.2014.04.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Revised: 04/02/2014] [Accepted: 04/14/2014] [Indexed: 12/20/2022]
Abstract
RET gene is crucial for the development of enteric nervous system, and dys-regulation of RET expression causes Hirschsprung disease. HOXB5 regulates RET transcription, and perturbations in transcriptional regulation by HOXB5 caused reduced RET expression and defective enteric nervous system development in mice. The mechanisms by which HOXB5 regulate RET transcription are unclear. Thus, unraveling the regulatory mechanisms of HOXB5 on RET transcription could lead to a better understanding of the etiology of Hirschsprung disease. In this study, we identified and confirmed HOXB5 binding to the multi-species conserved sequence (MCS+9.7) in the first intron of the RET gene. We developed a RET mini-gene reporter system, and showed that MCS+9.7 enhanced HOXB5 trans-activation from RET promoter in human neuroblastoma SK-N-SH cells and in chick embryos. The deletion of HOXB5 binding site interfered with HOXB5 trans-activation. Furthermore, transfection of HOXB5 induced endogenous RET transcription, enhanced the co-precipitation of TATA-box binding protein with the transcription start site of RET, and induced histone H3K4 trimethylation in chromatin regions upstream and downstream of RET transcription start site. In conclusion, (i) HOXB5 physically interacted with MCS+9.7 and enhanced RET transcription, (ii) HOXB5 altered chromatin conformation and histone modification of RET locus, which could facilitate the formation of transcription complex, and enhance RET transcription, (iii) expression of RET was mediated by a complex regulatory network of transcription factors functioning in a synergistic, additive and/or independent manners. Hence, dys-regulation of RET expression by HOXB5 could result in insufficient RET expression and Hirschsprung disease.
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Affiliation(s)
- Joe Jiang Zhu
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region; Faculty of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
| | - Mandy KaMan Kam
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region
| | - Maria-Mercè Garcia-Barceló
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region
| | - Paul Kwong Hang Tam
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region
| | - Vincent Chi Hang Lui
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region.
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Koldamova R, Schug J, Lefterova M, Cronican AA, Fitz NF, Davenport FA, Carter A, Castranio EL, Lefterov I. Genome-wide approaches reveal EGR1-controlled regulatory networks associated with neurodegeneration. Neurobiol Dis 2013; 63:107-14. [PMID: 24269917 DOI: 10.1016/j.nbd.2013.11.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 10/17/2013] [Accepted: 11/12/2013] [Indexed: 11/29/2022] Open
Abstract
Early growth response gene 1 (Egr1) is a member of the immediate early gene (IEG) family of transcription factors and plays a role in memory formation. To identify EGR1 target genes in brain of Alzheimer's disease (AD) model mice - APP23, we applied chromatin immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIP-seq). Functional annotation of genes associated with EGR1 binding revealed a set of related networks including synaptic vesicle transport, clathrin-mediated endocytosis (CME), intracellular membrane fusion and transmission of signals elicited by Ca(2+) influx. EGR1 binding is associated with significant enrichment of activating chromatin marks and appears enriched near genes that are up-regulated in the brains of APP23 mice. Among the putative EGR1 targets identified and validated in this study are genes related to synaptic plasticity and transport of proteins, such as Arc, Grin1, Syn2, Vamp2 and Stx6, and genes implicated in AD such as Picalm, Psen2 and App. We also demonstrate a potential regulatory link between EGR1 and its newly identified targets in vivo, since conditions that up-regulate Egr1 levels in brain, such as a spatial memory test, also lead to increased expression of the targets. On the other hand, protein levels of EGR1 and ARC, SYN2, STX6 and PICALM are significantly lower in the brain of adult APP mice than in age-matched wild type animals. The results of this study suggest that EGR1 regulates the expression of genes involved in CME, vesicular transport and synaptic transmission that may be critical for AD pathogenesis.
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Affiliation(s)
- Radosveta Koldamova
- Department of Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
| | - Jonathan Schug
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA; Functional Genomics Core, Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Martina Lefterova
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Andrea A Cronican
- Department of Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Nicholas F Fitz
- Department of Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Faith A Davenport
- Department of Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Alexis Carter
- Department of Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Emilie L Castranio
- Department of Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Iliya Lefterov
- Department of Environmental & Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
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D'Addario C, Di Francesco A, Pucci M, Finazzi Agrò A, Maccarrone M. Epigenetic mechanisms and endocannabinoid signalling. FEBS J 2013; 280:1905-17. [PMID: 23305292 DOI: 10.1111/febs.12125] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 12/23/2012] [Accepted: 01/07/2013] [Indexed: 12/28/2022]
Abstract
The endocannabinoid system, composed of endogenous lipids, their target receptors and metabolic enzymes, has been implicated in multiple biological functions in health and disease, both in the central nervous system and in peripheral organs. Despite the exponential growth of experimental evidence on the key role of endocannabinoid signalling in basic cellular processes, and on its potential exploitation for therapeutic interventions, much remains to be clarified about the respective regulatory mechanisms. Epigenetics refers to a set of post-translational modifications that regulate gene expression without causing variation in DNA sequence, endowed with a major impact on signal transduction pathways. The epigenetic machinery includes DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs. Due to the reversibility of epigenetic changes, an emerging field of interest is the possibility of an 'epigenetic therapy' that could possibly be applied also to endocannabinoids. Here, we review current knowledge of epigenetic regulation of endocannabinoid system components under both physiological and pathological conditions, as well as the epigenetic changes induced by endocannabinoid signalling.
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Affiliation(s)
- Claudio D'Addario
- Department of Biomedical Sciences, University of Teramo, Teramo, Italy.
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Cronican AA, Fitz NF, Carter A, Saleem M, Shiva S, Barchowsky A, Koldamova R, Schug J, Lefterov I. Genome-wide alteration of histone H3K9 acetylation pattern in mouse offspring prenatally exposed to arsenic. PLoS One 2013; 8:e53478. [PMID: 23405071 PMCID: PMC3566160 DOI: 10.1371/journal.pone.0053478] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 11/29/2012] [Indexed: 01/19/2023] Open
Abstract
Chronic exposure to arsenic in drinking water, especially in utero or perinatal exposure, can initiate neurological and cognitive dysfunction, as well as memory impairment. Several epidemiological studies have demonstrated cognitive and learning deficits in children with early exposure to low to moderate levels of arsenic, but pathogenic mechanisms or etiology for these deficits are poorly understood. Since in vivo studies show a role for histone acetylation in cognitive performance and memory formation, we examined if prenatal exposure to arsenic causes changes in the epigenomic landscape. We exposed C57Bl6/J mice to 100 μg/L arsenic in the drinking water starting 1 week before conception till birth and applied chromatin immunoprecipitation followed by high-throughput massive parallel sequencing (ChIP-seq) to evaluate H3K9 acetylation pattern in the offspring of exposed and control mice. Arsenic exposure during embryonic life caused global hypo-acetylation at H3K9 and changes in functional annotation with highly significant representation of Krüppel associated box (KRAB) transcription factors in brain samples from exposed pups. We also found that arsenic exposure of adult mice impaired spatial and episodic memory, as well as fear conditioning performance. This is the first study to demonstrate: a) genome wide changes in H3K9 acetylation pattern in an offspring prenatally exposed to arsenic, and b) a connection between moderate arsenic exposure and cognitive impairment in adult mice. The results also emphasize the applicability of Next Generation Sequencing methodology in studies aiming to reveal the role of environmental factors, other than dietary restriction, in developmental reprogramming through histone modifications during embryonic development.
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Affiliation(s)
- Andrea A. Cronican
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Nicholas F. Fitz
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Alexis Carter
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Muzamil Saleem
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Sruti Shiva
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Aaron Barchowsky
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Radosveta Koldamova
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Jonathan Schug
- Functional Genomics and Next-Generation Sequencing Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- * E-mail: (JS); (IL)
| | - Iliya Lefterov
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- * E-mail: (JS); (IL)
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Nicetto D, Hahn M, Jung J, Schneider TD, Straub T, David R, Schotta G, Rupp RAW. Suv4-20h histone methyltransferases promote neuroectodermal differentiation by silencing the pluripotency-associated Oct-25 gene. PLoS Genet 2013; 9:e1003188. [PMID: 23382689 PMCID: PMC3561085 DOI: 10.1371/journal.pgen.1003188] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Accepted: 11/07/2012] [Indexed: 01/31/2023] Open
Abstract
Post-translational modifications (PTMs) of histones exert fundamental roles in regulating gene expression. During development, groups of PTMs are constrained by unknown mechanisms into combinatorial patterns, which facilitate transitions from uncommitted embryonic cells into differentiated somatic cell lineages. Repressive histone modifications such as H3K9me3 or H3K27me3 have been investigated in detail, but the role of H4K20me3 in development is currently unknown. Here we show that Xenopus laevis Suv4-20h1 and h2 histone methyltransferases (HMTases) are essential for induction and differentiation of the neuroectoderm. Morpholino-mediated knockdown of the two HMTases leads to a selective and specific downregulation of genes controlling neural induction, thereby effectively blocking differentiation of the neuroectoderm. Global transcriptome analysis supports the notion that these effects arise from the transcriptional deregulation of specific genes rather than widespread, pleiotropic effects. Interestingly, morphant embryos fail to repress the Oct4-related Xenopus gene Oct-25. We validate Oct-25 as a direct target of xSu4-20h enzyme mediated gene repression, showing by chromatin immunoprecipitaton that it is decorated with the H4K20me3 mark downstream of the promoter in normal, but not in double-morphant, embryos. Since knockdown of Oct-25 protein significantly rescues the neural differentiation defect in xSuv4-20h double-morphant embryos, we conclude that the epistatic relationship between Suv4-20h enzymes and Oct-25 controls the transit from pluripotent to differentiation-competent neural cells. Consistent with these results in Xenopus, murine Suv4-20h1/h2 double-knockout embryonic stem (DKO ES) cells exhibit increased Oct4 protein levels before and during EB formation, and reveal a compromised and biased capacity for in vitro differentiation, when compared to normal ES cells. Together, these results suggest a regulatory mechanism, conserved between amphibians and mammals, in which H4K20me3-dependent restriction of specific POU-V genes directs cell fate decisions, when embryonic cells exit the pluripotent state. The quest of modern developmental biology is a detailed molecular description of the process that leads from the fertilized egg to the complex and highly differentiated adult organism. This process is controlled largely on the level of gene expression. While early embryonic cells are pluripotent and capable of transcribing most of their genome, older cells have become committed to the germ layer and differentiation programs during gastrulation. They express then a subset of genes compatible with their future physiological function. Young, pluripotent cells and post-gastrula, committed cells express different networks of transcription factors and contain chromatin of different structure and composition. How these two regulatory layers are interconnected during development is incompletely understood. We describe a novel and unexpected link between the pluripotency-associated POU-V gene Oct-25 and xSuv4-20h histone methyltransferases. XSuv4-20h enzymes are required to repress the Oct-25 gene, a homolog of mammalian Oct4, in the neuroectoderm of frog embryos as a prerequisite for neural differentiation. Consistently, murine Suv4-20h double-null ES cells show increased Oct4 protein levels before and during in vitro differentiation and display compromised differentiation in comparison to wild-type ES cells. Thus, Suv4-20h enzymes control specific POU-V genes and are involved in germ-layer specific differentiation.
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Affiliation(s)
- Dario Nicetto
- Adolf Butenandt Institut, Institut für Molekularbiologie, Ludwig Maximilians-Universität, München, Germany
| | - Matthias Hahn
- Center for Integrated Protein Science (Munich) at the Institut für Molekularbiologie, Adolf-Butenandt-Institut, LMU, München, Germany
| | - Julia Jung
- Medizinische Klinik I am Klinikum der Universität München (LMU), München, Germany
| | - Tobias D. Schneider
- Adolf Butenandt Institut, Institut für Molekularbiologie, Ludwig Maximilians-Universität, München, Germany
| | - Tobias Straub
- Adolf Butenandt Institut, Institut für Molekularbiologie, Ludwig Maximilians-Universität, München, Germany
| | - Robert David
- Medizinische Klinik I am Klinikum der Universität München (LMU), München, Germany
| | - Gunnar Schotta
- Center for Integrated Protein Science (Munich) at the Institut für Molekularbiologie, Adolf-Butenandt-Institut, LMU, München, Germany
| | - Ralph A. W. Rupp
- Adolf Butenandt Institut, Institut für Molekularbiologie, Ludwig Maximilians-Universität, München, Germany
- * E-mail:
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Sawicka A, Seiser C. Histone H3 phosphorylation - a versatile chromatin modification for different occasions. Biochimie 2012; 94:2193-201. [PMID: 22564826 PMCID: PMC3480636 DOI: 10.1016/j.biochi.2012.04.018] [Citation(s) in RCA: 152] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 04/16/2012] [Indexed: 12/11/2022]
Abstract
Post-translation modifications of histones modulate the accessibility and transcriptional competence of specific chromatin regions within the eukaryotic genome. Phosphorylation of histone H3 is unique in the sense that it associates on one hand with open chromatin during gene activation and marks on the other hand highly condensed chromatin during mitosis. Phosphorylation of serine residues at histone H3 is a highly dynamic process that creates together with acetylation and methylation marks at neighboring lysine residues specific combinatorial patterns that are read by specific detector proteins. In this review we describe the importance of different histone H3 phosphorylation marks for chromatin condensation during mitosis. In addition, we review the signals that trigger histone H3 phosphorylation and the factors that control this reversible modification during interphase and mediate the biological readout of the signal. Finally, we discuss different models describing the role of histone H3 phosphorylation in the activation of transcription of poised genes or by transient derepression of epigenetically silenced genes. We propose that histone H3 phosphorylation in the context with lysine methylation might temporarily relieve the silencing of specific genes without affecting the epigenetic memory.
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Affiliation(s)
| | - Christian Seiser
- Department of Medical Biochemistry, Max F. Perutz Laboratories, Vienna Biocenter, Medical University of Vienna, Dr. Bohr-Gasse 9/2, A-1030 Vienna, Austria
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32
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Goode DK, Elgar G. Capturing the regulatory interactions of eukaryote genomes. Brief Funct Genomics 2012; 12:142-60. [PMID: 23117864 DOI: 10.1093/bfgp/els041] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
A key finding from early genomics research is the remarkable consistency in the number of protein-coding regions across diverse species. This has led many researchers to look to the cis-regulatory elements of genes as the fundamental influence behind evolving gene function and subsequent species diversification. Historically, since these elements are often located in vast intergenic and intronic regions of the genome, their identification has been recalcitrant. Now, with the deluge of whole-genome data from representatives of numerous eukaryotic lineages, various approaches have enabled us to begin to recognize features that characterize regulatory regions of the genome. Here we endeavour to collate these approaches in order to give an overview of the complexities involved in extrapolating regulatory signatures. The resource provided by the escalating richness of whole-genome datasets enables more sophisticated modelling of these regulatory signatures yet at the same time introduces increasing potential for noise. While we are only at the advent of making these discoveries, the next decade promises to be a very exciting and rewarding time for genome researchers.
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Affiliation(s)
- Debbie K Goode
- Cambridge Institute for Medical Research, Deptartment of Haematology, Addenbrooke's Hospital, Hills Road, Cambridge, UK
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Gupta J, Kumar S, Li J, Krishna Murthy Karuturi R, Tikoo K. Histone H3 lysine 4 monomethylation (H3K4me1) and H3 lysine 9 monomethylation (H3K9me1): distribution and their association in regulating gene expression under hyperglycaemic/hyperinsulinemic conditions in 3T3 cells. Biochimie 2012; 94:2656-64. [PMID: 22951486 DOI: 10.1016/j.biochi.2012.08.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 08/02/2012] [Indexed: 10/28/2022]
Abstract
Hyperglycemia/hyperinsulinemia are leading cause for the induction type 2 diabetes and the role of post-translational histone modifications in dysregulating the expression of genes has emerged as potential important contributor in the progression of disease. The paradoxical nature of histone H3-Lysine 4 and Lysine 9 mono-methylation (H3K4me1 and H3K9me1) in both gene activation and repression motivated us to elucidate the functional relationship of these histone modifications in regulating expression of genes under hyperglycaemic/hyperinsulinemic condition. Chromatin immunoprecipitation-microarray analysis (ChIP-chip) was performed with H3 acetylation, H3K4me1 and H3K9me1 antibody. CLUSTER analysis of ChIP-chip (Chromatin immunoprecipitation-microarray analysis) data showed that mRNA expression and H3 acetylation/H3K4me1 levels on genes were inversely correlated with H3K9me1 levels on the transcribed regions, after 30 min of insulin stimulation under hyperglycaemic condition. Interestingly, we provide first evidence regarding regulation of histone de/acetylases and de/methylases; Myst4, Jmjd2b, Aof1 and Set by H3Ac, H3K4me1 and H3K9me1 under hyperinsulinemic/hyperglycaemic condition. ChIP-qPCR analysis shows association of increased H3Ac/H3K4me1 and decreased levels of H3K9me1 in up regulation of Myst4, Jmjd2, Set and Aof1 genes. We further analyse promoter occupancy of histone modifications by ChIP walking and observed increased occupancy of H3Ac/H3K4me1 on promoter region (-1000 to -1) of active genes and H3K9me1 on inactive genes under hyperglycemic/hyperinsulinemic condition. To best of our knowledge this is the first report that shows regulation of chromatin remodelling genes by alteration in the occupancy of histone H3Ac/H3K4/K9me on both promoter and transcribed regions.
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Affiliation(s)
- Jeena Gupta
- Laboratory of Chromatin Biology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Mohali, Punjab, India
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Epigenetic impact of dietary polyphenols in cancer chemoprevention: Lifelong remodeling of our epigenomes. Pharmacol Res 2012; 65:565-76. [DOI: 10.1016/j.phrs.2012.03.007] [Citation(s) in RCA: 183] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 03/10/2012] [Accepted: 03/13/2012] [Indexed: 02/07/2023]
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Hsu DW, Chubb JR, Muramoto T, Pears CJ, Mahadevan LC. Dynamic acetylation of lysine-4-trimethylated histone H3 and H3 variant biology in a simple multicellular eukaryote. Nucleic Acids Res 2012; 40:7247-56. [PMID: 22600736 PMCID: PMC3424546 DOI: 10.1093/nar/gks367] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Dynamic acetylation of all lysine-4-trimethylated histone H3 is a complex phenomenon involved in Immediate-early gene induction in metazoan eukaryotes. Higher eukaryotes express repeated copies of three closely related H3 variants, inaccessible to genetic analysis. We demonstrate conservation of these phenomena in Dictyostelium which has three single-copy H3 variant genes. Although dynamic acetylation is targeted to two H3 variants which are K4-trimethylated, K9-acetylation is preferentially targeted to one. In cells lacking Set1 methyltransferase and any detectable K4-trimethylation, dynamic acetylation is lost demonstrating a direct link between the two. Gene replacement to express mutated H3 variants reveals a novel interaction between K4-trimethylation on different variants. Cells expressing only one variant show defects in growth, and in induction of a UV-inducible gene, demonstrating the functional importance of variant expression. These studies confirm that dynamic acetylation targeted to H3K4me3 arose early in evolution and reveal a very high level of specificity of histone variant utilization in a simple multicellular eukaryote.
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Affiliation(s)
- Duen-Wei Hsu
- Nuclear Signalling Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
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Srivastava S, Mishra RK, Dhawan J. Regulation of cellular chromatin state: insights from quiescence and differentiation. Organogenesis 2012; 6:37-47. [PMID: 20592864 DOI: 10.4161/org.6.1.11337] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2009] [Revised: 01/19/2010] [Accepted: 01/29/2010] [Indexed: 11/19/2022] Open
Abstract
The identity and functionality of eukaryotic cells is defined not just by their genomic sequence which remains constant between cell types, but by their gene expression profiles governed by epigenetic mechanisms. Epigenetic controls maintain and change the chromatin state throughout development, as exemplified by the setting up of cellular memory for the regulation and maintenance of homeotic genes in proliferating progenitors during embryonic development. Higher order chromatin structure in reversibly arrested adult stem cells also involves epigenetic regulation and in this review we highlight common trends governing chromatin states, focusing on quiescence and differentiation during myogenesis. Together, these diverse developmental modules reveal the dynamic nature of chromatin regulation providing fresh insights into the role of epigenetic mechanisms in potentiating development and differentiation.
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Affiliation(s)
- Surabhi Srivastava
- Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India.
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37
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Wang X, Bishop KA, Hegde S, Rodenkirch LA, Pike JW, Gumperz JE. Human invariant natural killer T cells acquire transient innate responsiveness via histone H4 acetylation induced by weak TCR stimulation. ACTA ACUST UNITED AC 2012; 209:987-1000. [PMID: 22508835 PMCID: PMC3348100 DOI: 10.1084/jem.20111024] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Weak TCR stimulation of iNKT cells, such as that resulting from self-antigen recognition, induces histone modifications at the IFNG locus that allow the iNKT cells to subsequently produce IFN-γ in response to proinflammatory cytokines alone. Invariant NKT cells (iNKT cells) are innate T lymphocytes that are thought to play an important role in producing an early burst of IFN-γ that promotes successful tumor immunosurveillance and antimicrobial immunity. The cellular activation processes underlying innate IFN-γ production remain poorly understood. We show here that weak T cell receptor (TCR) stimulation that does not directly activate iNKT cell IFN-γ messenger RNA transcription nevertheless induces histone H4 acetylation at specific regions near the IFNG gene locus. This renders the iNKT cells able to produce IFN-γ in an innate manner (i.e., not requiring concurrent TCR stimulation) upon exposure to IL-12 and IL-18. The iNKT cells retain the capacity for innate activation for hours to days after the initial weak TCR stimulation, although their innate responsiveness gradually declines as a function of histone deacetylation. These results explain how iNKT cells are able to mediate rapid innate IFN-γ secretion in a manner that does not require them to undergo permanent TH1 differentiation. Moreover, our results also indicate that iNKT cell motility is maintained during activation by IL-12 and IL-18. Therefore, iNKT cells activated through this pathway can continue to migrate and may thus disseminate the IFN-γ that they produce, which may amplify its impact.
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Affiliation(s)
- Xiaohua Wang
- Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA
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38
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Lim PS, Shannon MF, Hardy K. Epigenetic control of inducible gene expression in the immune system. Epigenomics 2012; 2:775-95. [PMID: 22122082 DOI: 10.2217/epi.10.55] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
It has been well documented that active genes, and their promoters and enhancers have a different chromatin or epigenomic environment compared with unexpressed genes. In addition, the epigenome may influence not only which genes are expressed, but also which genes can be induced in response to activation or differentiation signals. Immune cells respond to activation signals by rapidly inducing the expression of specific gene sets, and therefore this is a good system in which to examine the role of the epigenome in gene activation and cell differentiation. Several studies have now found that many immediate-early inducible genes exist in a similar epigenomic environment to active genes even in the unstimulated state. Some studies suggest that subsets of these genes may even have RNA polymerase II at their promoters and induction may be controlled downstream of its recruitment. Other inducible genes, however, undergo changes to histone modifications, levels or variant composition upon activation. In this article, we discuss how the epigenome of immune cells regulates inducible gene expression and discuss the differences between the immediate responses to activation signals and the longer term changes observed during differentiation.
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Affiliation(s)
- Pek Siew Lim
- Department of Genome Biology, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2601, Australia
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39
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Kooistra SM, Helin K. Molecular mechanisms and potential functions of histone demethylases. Nat Rev Mol Cell Biol 2012; 13:297-311. [PMID: 22473470 DOI: 10.1038/nrm3327] [Citation(s) in RCA: 653] [Impact Index Per Article: 50.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Histone modifications are thought to regulate chromatin structure, transcription and other nuclear processes. Histone methylation was originally believed to be an irreversible modification that could only be removed by histone eviction or by dilution during DNA replication. However, the isolation of two families of enzymes that can demethylate histones has changed this notion. The biochemical activities of these histone demethylases towards specific Lys residues on histones, and in some cases non-histone substrates, have highlighted their importance in developmental control, cell-fate decisions and disease. Their ability to be regulated through protein-targeting complexes and post-translational modifications is also beginning to shed light on how they provide dynamic control during transcription.
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Affiliation(s)
- Susanne Marije Kooistra
- Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark
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40
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Ettig R, Kepper N, Stehr R, Wedemann G, Rippe K. Dissecting DNA-histone interactions in the nucleosome by molecular dynamics simulations of DNA unwrapping. Biophys J 2012; 101:1999-2008. [PMID: 22004754 DOI: 10.1016/j.bpj.2011.07.057] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2011] [Revised: 07/17/2011] [Accepted: 07/27/2011] [Indexed: 11/25/2022] Open
Abstract
The nucleosome complex of DNA wrapped around a histone protein octamer organizes the genome of eukaryotes and regulates the access of protein factors to the DNA. We performed molecular dynamics simulations of the nucleosome in explicit water to study the dynamics of its histone-DNA interactions. A high-resolution histone-DNA interaction map was derived that revealed a five-nucleotide periodicity, in which the two DNA strands of the double helix made alternating contacts. On the 100-ns timescale, the histone tails mostly maintained their initial positions relative to the DNA, and the spontaneous unwrapping of DNA was limited to 1-2 basepairs. In steered molecular dynamics simulations, external forces were applied to the linker DNA to investigate the unwrapping pathway of the nucleosomal DNA. In comparison with a nucleosome without the unstructured N-terminal histone tails, the following findings were obtained: 1), Two main barriers during unwrapping were identified at DNA position ±70 and ±45 basepairs relative to the central DNA basepair at the dyad axis. 2), DNA interactions of the histone H3 N-terminus and the histone H2A C-terminus opposed the initiation of unwrapping. 3), The N-terminal tails of H2A, H2B, and H4 counteracted the unwrapping process at later stages and were essential determinants of nucleosome dynamics. Our detailed analysis of DNA-histone interactions revealed molecular mechanisms for modulating access to nucleosomal DNA via conformational rearrangements of its structure.
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Affiliation(s)
- Ramona Ettig
- Deutsches Krebsforschungszentrum (DKFZ) and BioQuant, Research Group Genome Organization & Function, Heidelberg, Germany
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41
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Pandya K, Kohro T, Mimura I, Kobayashi M, Wada Y, Kodama T, Smithies O. Distribution of histone3 lysine 4 trimethylation at T3-responsive loci in the heart during reversible changes in gene expression. Gene Expr 2012; 15:183-98. [PMID: 22783727 PMCID: PMC3607203 DOI: 10.3727/105221612x13372578119698] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Expression in the adult heart of a number of cardiac genes, including the two genes comprising the cardiac myosin heavy chain locus (Myh), is controlled by thyroid hormone (T3) levels, but there is minimal information concerning the epigenetic status of the genes when their expressions change. We fed mice normal chow or a propyl thio uracil (PTU, an inhibitor of T3 production) diet for 6 weeks, or the PTU diet for 6 weeks followed by normal chow for a further 2 weeks. Heart ventricles from these groups were then used for ChIP-seq analyses with an antibody to H3K4me3, a well-documented epigenetic marker of gene activation. The resulting data show that, at the Myh7 locus, H3K4me3 modifications are induced primarily at 5' transcribed region in parallel with increased expression of beta myosin heavy chain (MHC). At the Myh6 locus, decreases in H3K4me3 modifications occurred at the promoter and 5' transcribed region. Extensive H3K4me3 modifications also occurred at the intergenic region between the two Myh genes, which extended into the 3' transcribed region of Myh7. The PTU-induced changes in H3K4me3 levels are, for the most part, reversible but are not invariably complete. We found full restoration of Myh6 gene expression upon PTU withdrawal; however, the H3K4me3 pattern was only partially restored at Myh6, suggesting that full reexpression of Myh6 does not require that the H3K4me3 modifications return fully to the untreated conditions. Together, our data show that the H3K4me3 modification is an epigenetic marker closely associated with changes in Myh gene expression.
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Affiliation(s)
- Kumar Pandya
- *Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Takahide Kohro
- †Department of Molecular Biology and Medicine, The Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Imari Mimura
- †Department of Molecular Biology and Medicine, The Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Mika Kobayashi
- †Department of Molecular Biology and Medicine, The Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Youichiro Wada
- †Department of Molecular Biology and Medicine, The Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Tatsuhiko Kodama
- †Department of Molecular Biology and Medicine, The Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Oliver Smithies
- *Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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42
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Abstract
The vitamin folate functions within the cell as a carrier of one-carbon units. The requirement for one-carbon transfers is ubiquitous and all mammalian cells carry out folate dependent reactions. In recent years, low folate status has been linked to risk of numerous adverse health conditions throughout life from birth defects and complications of pregnancy to cardiovascular disease, cancer and cognitive dysfunction in the elderly. In many instances inadequate intake of folate seems to be the primary contributor but there is also evidence that an underlying genetic susceptibility can play a modest role by causing subtle alterations in the availability, metabolism or distribution of intermediates in folate related pathways. Folate linked one-carbon units are essential for DNA synthesis and repair and as a source of methyl groups for biological methylation reactions. The notion of common genetic variants being linked to risk of disease was relatively novel in 1995 when the first functional folate-related polymorphism was discovered. Numerous polymorphisms have now been identified in folate related genes and have been tested for functionality either as a modifier of folate status or as being associated with risk of disease. Moreover, there is increasing research into the importance of folate-derived one-carbon units for DNA and histone methylation reactions, which exert crucial epigenetic control over cellular protein synthesis. It is thus becoming clear that genetic aspects of folate metabolism are wide-ranging and may touch on events as disparate as prenatal imprinting to cancer susceptibility. This chapter will review the current knowledge in this area.
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Affiliation(s)
- Anne M Molloy
- School of Medicine, Trinity College Dublin, Dublin 2, Ireland,
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Cheng C, Gerstein M. Modeling the relative relationship of transcription factor binding and histone modifications to gene expression levels in mouse embryonic stem cells. Nucleic Acids Res 2011; 40:553-68. [PMID: 21926158 PMCID: PMC3258143 DOI: 10.1093/nar/gkr752] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Transcription factor (TF) binding and histone modification (HM) are important for the precise control of gene expression. Hence, we constructed statistical models to relate these to gene expression levels in mouse embryonic stem cells. While both TF binding and HMs are highly ‘predictive’ of gene expression levels (in a statistical, but perhaps not strictly mechanistic, sense), we find they show distinct differences in the spatial patterning of their predictive strength: TF binding achieved the highest predictive power in a small DNA region centered at the transcription start sites of genes, while the HMs exhibited high predictive powers across a wide region around genes. Intriguingly, our results suggest that TF binding and HMs are redundant in strict statistical sense for predicting gene expression. We also show that our TF and HM models are cell line specific; specifically, TF binding and HM are more predictive of gene expression in the same cell line, and the differential gene expression between cell lines is predictable by differential HMs. Finally, we found that the models trained solely on protein-coding genes are predictive of expression levels of microRNAs, suggesting that their regulation by TFs and HMs may share a similar mechanism to that for protein-coding genes.
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Affiliation(s)
- Chao Cheng
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA
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44
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Barrachina M, Moreno J, Villar-Menéndez I, Juvés S, Ferrer I. Histone tail acetylation in brain occurs in an unpredictable fashion after death. Cell Tissue Bank 2011; 13:597-606. [PMID: 21922206 DOI: 10.1007/s10561-011-9278-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2011] [Accepted: 09/08/2011] [Indexed: 10/17/2022]
Abstract
Histone acetylation plays a role in the regulation of gene transcription. Yet it is not known whether post-mortem brain tissue is suitable for the analysis of histone acetylation. To examine this question, nucleosomes were isolated from frontal cortex of nine subjects which were obtained at short times after death and immediately frozen at -80°C or maintained at room temperature from 3 h up to 50 h after death and then frozen at -80°C to mimic variable post-mortem delay in tissue processing as currently occurs in normal practice. Chromatin immunoprecipitation assays were performed for two lysine residues, H3K9ac and H3K27ac. Four gene loci were amplified by SyBrGreen PCR: Adenosine A(2A) receptor, UCHL1, α-synuclein and β-globin. Results showed variability in the histone acetylation level along the post-mortem times and an increase in the acetylation level at an unpredictable time from one case to another and from one gene to another within the first 24 h of post-mortem delay. Similar results were found with three rat brains used to exclude the effects of agonal state and to normalize the start-point as real time zero. Therefore, the present observations show that human post-mortem brain is probably not suitable for comparative studies of histone acetylation.
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Affiliation(s)
- Marta Barrachina
- Institute of Neuropathology, [Bellvitge Biomedical Research Institute-] IDIBELL, Bellvitge University Hospital-ICS, c/Feixa Llarga s/n, 08908 L'Hospitalet de Llobregat, Spain.
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45
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Heightman TD. Chemical biology of lysine demethylases. CURRENT CHEMICAL GENOMICS 2011; 5:62-71. [PMID: 21966346 PMCID: PMC3178875 DOI: 10.2174/1875397301005010062] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2011] [Revised: 04/12/2011] [Accepted: 04/25/2011] [Indexed: 11/22/2022]
Abstract
Abnormal levels of DNA methylation and/or histone modifications are observed in patients with a wide variety of chronic diseases. Methylation of lysines within histone tails is a key modification that contributes to increased gene expression or repression depending on the specific residue and degree of methylation, which is in turn controlled by the interplay of lysine methyl transferases and demethylases. Drugs that target these and other enzymes controlling chromatin modifications can modulate the expression of clusters of genes, potentially offering higher therapeutic efficacy than classical agents acting on downstream biochemical pathways that are susceptible to degeneracy. Lysine demethylases, first discovered in 2004, are the subject of increasing interest as therapeutic targets. This review provides an overview of recent findings implicating lysine demethylases in a range of therapeutic areas including oncology, immunoinflammation, metabolic disorders, neuroscience, virology and regenerative medicine, together with a summary of recent advances in structural biology and small molecule inhibitor discovery, supporting the tractability of the protein family for the development of selective druglike inhibitors.
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Affiliation(s)
- Tom D Heightman
- Structural Genomics Consortium, Oxford University, Roosevelt Drive, Oxford OX3 7DQ, UK
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46
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Schneider TD, Arteaga-Salas JM, Mentele E, David R, Nicetto D, Imhof A, Rupp RAW. Stage-specific histone modification profiles reveal global transitions in the Xenopus embryonic epigenome. PLoS One 2011; 6:e22548. [PMID: 21814581 PMCID: PMC3142184 DOI: 10.1371/journal.pone.0022548] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2011] [Accepted: 06/29/2011] [Indexed: 02/03/2023] Open
Abstract
Vertebrate embryos are derived from a transitory pool of pluripotent cells. By the process of embryonic induction, these precursor cells are assigned to specific fates and differentiation programs. Histone post-translational modifications are thought to play a key role in the establishment and maintenance of stable gene expression patterns underlying these processes. While on gene level histone modifications are known to change during differentiation, very little is known about the quantitative fluctuations in bulk histone modifications during development. To investigate this issue we analysed histones isolated from four different developmental stages of Xenopus laevis by mass spectrometry. In toto, we quantified 59 modification states on core histones H3 and H4 from blastula to tadpole stages. During this developmental period, we observed in general an increase in the unmodified states, and a shift from histone modifications associated with transcriptional activity to transcriptionally repressive histone marks. We also compared these naturally occurring patterns with the histone modifications of murine ES cells, detecting large differences in the methylation patterns of histone H3 lysines 27 and 36 between pluripotent ES cells and pluripotent cells from Xenopus blastulae. By combining all detected modification transitions we could cluster their patterns according to their embryonic origin, defining specific histone modification profiles (HMPs) for each developmental stage. To our knowledge, this data set represents the first compendium of covalent histone modifications and their quantitative flux during normogenesis in a vertebrate model organism. The HMPs indicate a stepwise maturation of the embryonic epigenome, which may be causal to the progressing restriction of cellular potency during development.
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Affiliation(s)
- Tobias D Schneider
- Department of Molecular Biology, Adolf-Butenandt Institut, Ludwig-Maximilians-Universität München, Munich, Germany
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Erdel F, Krug J, Längst G, Rippe K. Targeting chromatin remodelers: signals and search mechanisms. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2011; 1809:497-508. [PMID: 21704204 DOI: 10.1016/j.bbagrm.2011.06.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2011] [Revised: 06/02/2011] [Accepted: 06/06/2011] [Indexed: 12/26/2022]
Abstract
Chromatin remodeling complexes are ATP-driven molecular machines that change chromatin structure by translocating nucleosomes along the DNA, evicting nucleosomes, or changing the nucleosomal histone composition. They are highly abundant in the cell and numerous different complexes exist that display distinct activity patterns. Here we review chromatin-associated signals that are recognized by remodelers. It is discussed how these regulate the remodeling reaction via changing the nucleosome substrate/product binding affinity or the catalytic translocation rate. Finally, we address the question of how chromatin remodelers operate in the cell nucleus to find specifically marked nucleosome substrates via a diffusion driven target location mechanism, and estimate the search times of this process. This article is part of a Special Issue entitled:Snf2/Swi2 ATPase structure and function.
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Affiliation(s)
- Fabian Erdel
- Research Group Genome Organization & Function, Deutsches Krebsforschungszentrum (DKFZ) & BioQuant, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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48
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Erdel F, Müller-Ott K, Baum M, Wachsmuth M, Rippe K. Dissecting chromatin interactions in living cells from protein mobility maps. Chromosome Res 2011; 19:99-115. [PMID: 20848178 DOI: 10.1007/s10577-010-9155-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The genome of eukaryotes is organized into a dynamic nucleoprotein complex referred to as chromatin, which can adopt different functional states. Both the DNA and the protein component of chromatin are subject to various post-translational modifications that define the cell's gene expression program. Their readout and establishment occurs in a spatio-temporally coordinated manner that is controlled by numerous chromatin-interacting proteins. Binding to chromatin in living cells can be measured by a spatially resolved analysis of protein mobility using fluorescence microscopy based approaches. Recent advancements in the acquisition of protein mobility data using fluorescence bleaching and correlation methods provide data sets on diffusion coefficients, binding kinetics, and cellular concentrations on different time and length scales. The combination of different techniques is needed to dissect the complex interplay of diffusive translocations, binding events, and mobility constraints of the chromatin environment. While bleaching techniques have their strength in the characterization of particles that are immobile on the second/minute time scale, a correlation analysis is advantageous to characterize transient binding events with millisecond residence time. The application and synergy effects of the different approaches to obtain protein mobility and interaction maps in the nucleus are illustrated for the analysis of heterochromatin protein 1.
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Affiliation(s)
- Fabian Erdel
- Deutsches Krebsforschungszentrum and BioQuant, Research Group Genome Organization and Function, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
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49
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Dynamic acetylation of all lysine-4 trimethylated histone H3 is evolutionarily conserved and mediated by p300/CBP. Proc Natl Acad Sci U S A 2011; 108:7814-9. [PMID: 21518915 DOI: 10.1073/pnas.1100099108] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Histone modifications are reported to show different behaviors, associations, and functions in different genomic niches and organisms. We show here that rapid, continuous turnover of acetylation specifically targeted to all K4-trimethylated H3 tails (H3K4me3), but not to bulk histone H3 or H3 carrying other methylated lysines, is a common uniform characteristic of chromatin biology in higher eukaryotes, being precisely conserved in human, mouse, and Drosophila. Furthermore, dynamic acetylation targeted to H3K4me3 is mediated by the same lysine acetyltransferase, p300/cAMP response element binding (CREB)-binding protein (CBP), in both mouse and fly cells. RNA interference or chemical inhibition of p300/CBP using a newly discovered small molecule inhibitor, C646, blocks dynamic acetylation of H3K4me3 globally in mouse and fly cells, and locally across the promoter and start-site of inducible genes in the mouse, thereby disrupting RNA polymerase II association and the activation of these genes. Thus, rapid dynamic acetylation of all H3K4me3 mediated by p300/CBP is a general, evolutionarily conserved phenomenon playing an essential role in the induction of immediate-early (IE) genes. These studies indicate a more global function of p300/CBP in mediating rapid turnover of acetylation of all H3K4me3 across the nuclei of higher eukaryotes, rather than a tight promoter-restricted function targeted by complex formation with specific transcription factors.
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50
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Banine F, Matagne V, Sherman LS, Ojeda SR. Brain region-specific expression of Fxyd1, an Mecp2 target gene, is regulated by epigenetic mechanisms. J Neurosci Res 2011; 89:840-51. [PMID: 21394759 DOI: 10.1002/jnr.22608] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2010] [Revised: 12/23/2010] [Accepted: 01/13/2011] [Indexed: 12/25/2022]
Abstract
Fxyd1 encodes a trans-membrane protein that modulates Na(+) ,K(+) -ATPase activity and is a substrate for multiple protein kinases. Fxyd1 expression is repressed by methyl CpG-binding protein 2 (Mecp2) in the frontal cortex (FC) but not in the cerebellum (CB) of the mouse brain. Consistently with these observations, FXYD1 mRNA abundance is increased in the FC of Rett syndrome (RTT) patients with MECP2 mutations. Because Fxyd1 is implicated in the regulation of neuronal excitability, understanding how Fxyd1 expression is controlled is important. Here we report that basal expression of Fxyd1a and Fxyd1b, the two main alternatively spliced forms of Fxyd1 mRNA, is lower in the FC than in the CB. This difference is accompanied by increased Mecp2 recruitment to the promoter region of these two Fxyd1 mRNA forms. DNA methylation of both promoters is more frequent in the FC than in the CB, and in both cases the most frequently methylated CpG dinucleotides are adjacent to [A/T](4) sequences required for high-affinity Mecp2 binding. Consistently with these features of epigenetic silencing, histone 3 acetylated at lysines 9 and 14 (H3K9/14ac) and histone 3 methylated at lysine 4 (H3K4me3), both activating histone marks, were associated with the Fxyd1 promoter to a lesser degree in the FC than in the CB. These results indicate that differential Fxyd1 expression in these two brain regions is, at least in part, regulated by an epigenetic mechanism involving increased DNA methylation of the two alternative Fxyd1 promoters, enhanced Mecp2 recruitment, and reduced association of activating histones.
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Affiliation(s)
- Fatima Banine
- Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, USA
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