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1
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Ibrahim SY, Carter J, Bagchi RA. Histone Deacetylases in Metabolism: the Known and the Unexplored. Physiology (Bethesda) 2025; 40:0. [PMID: 39470602 DOI: 10.1152/physiol.00044.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/04/2024] [Accepted: 10/21/2024] [Indexed: 10/30/2024] Open
Abstract
Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from key lysine residues on histone and nonhistone proteins and thereby regulate gene transcription. They have been implicated in several biological processes in both healthy and pathological settings. This review discusses the role of HDACs in multiple metabolically active tissues and highlights their contribution to the pathogenesis of tissue-specific maladaptation and diseases. We also summarize the current knowledge gaps and potential ways to address them in future studies.
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Affiliation(s)
- Somaya Y Ibrahim
- College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
- Department of Physiology and Cell Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
| | - Jayden Carter
- Department of Physiology and Cell Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
| | - Rushita A Bagchi
- Department of Physiology and Cell Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
- Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
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2
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Inserra A, Campanale A, Rezai T, Romualdi P, Rubino T. Epigenetic mechanisms of rapid-acting antidepressants. Transl Psychiatry 2024; 14:359. [PMID: 39231927 PMCID: PMC11375021 DOI: 10.1038/s41398-024-03055-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 08/19/2024] [Accepted: 08/21/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND Rapid-acting antidepressants (RAADs), including dissociative anesthetics, psychedelics, and empathogens, elicit rapid and sustained therapeutic improvements in psychiatric disorders by purportedly modulating neuroplasticity, neurotransmission, and immunity. These outcomes may be mediated by, or result in, an acute and/or sustained entrainment of epigenetic processes, which remodel chromatin structure and alter DNA accessibility to regulate gene expression. METHODS In this perspective, we present an overview of the known mechanisms, knowledge gaps, and future directions surrounding the epigenetic effects of RAADs, with a focus on the regulation of stress-responsive DNA and brain regions, and on the comparison with conventional antidepressants. MAIN BODY Preliminary correlative evidence indicates that administration of RAADs is accompanied by epigenetic effects which are similar to those elicited by conventional antidepressants. These include changes in DNA methylation, post-translational modifications of histones, and differential regulation of non-coding RNAs in stress-responsive chromatin areas involved in neurotrophism, neurotransmission, and immunomodulation, in stress-responsive brain regions. Whether these epigenetic changes causally contribute to the therapeutic effects of RAADs, are a consequence thereof, or are unrelated, remains unknown. Moreover, the potential cell type-specificity and mechanisms involved are yet to be fully elucidated. Candidate mechanisms include neuronal activity- and serotonin and Tropomyosine Receptor Kinase B (TRKB) signaling-mediated epigenetic changes, and direct interaction with DNA, histones, or chromatin remodeling complexes. CONCLUSION Correlative evidence suggests that epigenetic changes induced by RAADs accompany therapeutic and side effects, although causation, mechanisms, and cell type-specificity remain largely unknown. Addressing these research gaps may lead to the development of novel neuroepigenetics-based precision therapeutics.
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Affiliation(s)
- Antonio Inserra
- Department of Psychiatry, McGill University, Montreal, QC, Canada.
- Behavioral Neuroscience Laboratory, University of South Santa Catarina (UNISUL), Tubarão, Brazil., Tubarão, Brazil.
| | | | - Tamim Rezai
- Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - Patrizia Romualdi
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Tiziana Rubino
- Department of Biotechnology and Life Sciences and Neuroscience Center, University of Insubria, Varese, Italy
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3
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Kunoh S, Nakashima H, Nakashima K. Epigenetic Regulation of Neural Stem Cells in Developmental and Adult Stages. EPIGENOMES 2024; 8:22. [PMID: 38920623 PMCID: PMC11203245 DOI: 10.3390/epigenomes8020022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 05/18/2024] [Accepted: 05/31/2024] [Indexed: 06/27/2024] Open
Abstract
The development of the nervous system is regulated by numerous intracellular molecules and cellular signals that interact temporally and spatially with the extracellular microenvironment. The three major cell types in the brain, i.e., neurons and two types of glial cells (astrocytes and oligodendrocytes), are generated from common multipotent neural stem cells (NSCs) throughout life. However, NSCs do not have this multipotentiality from the beginning. During cortical development, NSCs sequentially obtain abilities to differentiate into neurons and glial cells in response to combinations of spatiotemporally modulated cell-intrinsic epigenetic alterations and extrinsic factors. After the completion of brain development, a limited population of NSCs remains in the adult brain and continues to produce neurons (adult neurogenesis), thus contributing to learning and memory. Many biological aspects of brain development and adult neurogenesis are regulated by epigenetic changes via behavioral control of NSCs. Epigenetic dysregulation has also been implicated in the pathogenesis of various brain diseases. Here, we present recent advances in the epigenetic regulation of NSC behavior and its dysregulation in brain disorders.
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Affiliation(s)
| | - Hideyuki Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
| | - Kinichi Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
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4
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Goodkey K, Wischmeijer A, Perrin L, Watson AES, Qureshi L, Cordelli DM, Toni F, Gnazzo M, Benedicenti F, Elmaleh-Bergès M, Low KJ, Voronova A. Olfactory bulb anomalies in KBG syndrome mouse model and patients. BMC Med 2024; 22:158. [PMID: 38616269 PMCID: PMC11017579 DOI: 10.1186/s12916-024-03363-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 03/18/2024] [Indexed: 04/16/2024] Open
Abstract
ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11-deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.
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Affiliation(s)
- Kara Goodkey
- Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
- Women and Children's Health Research Institute, University of Alberta, 5-083 Edmonton Clinic Health Academy, Edmonton, AB, T6G 1C9, Canada
| | - Anita Wischmeijer
- Clinical Genetics Service and Coordination Center for Rare Diseases, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy
| | | | - Adrianne E S Watson
- Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
- Women and Children's Health Research Institute, University of Alberta, 5-083 Edmonton Clinic Health Academy, Edmonton, AB, T6G 1C9, Canada
| | - Leenah Qureshi
- Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
| | - Duccio Maria Cordelli
- IRCCS Istituto Delle Scienze Neurologiche Di Bologna, UOC Neuropsichiatria Dell'età Pediatrica, Bologna, Italy
| | - Francesco Toni
- IRCCS Istituto Delle Scienze Neurologiche Di Bologna, Programma Di Neuroradiologia Con Tecniche Ad Elevata Complessità (PNTEC), Bologna, Italy
| | - Maria Gnazzo
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165, Rome, Italy
| | - Francesco Benedicenti
- Clinical Genetics Service and Coordination Center for Rare Diseases, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy
| | | | - Karen J Low
- Department of Academic Child Health, Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK
- Clinical Genetics Service, St. Michaels Hospital, Bristol, UK
| | - Anastassia Voronova
- Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
- Women and Children's Health Research Institute, University of Alberta, 5-083 Edmonton Clinic Health Academy, Edmonton, AB, T6G 1C9, Canada.
- Department of Cell Biology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
- Faculty of Medicine & Dentistry, Neuroscience and Mental Health Institute, Edmonton, AB, T6G 2E1, Canada.
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5
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Fukuda M, Fujita Y, Hino Y, Nakao M, Shirahige K, Yamashita T. Inhibition of HDAC8 Reduces the Proliferation of Adult Neural Stem Cells in the Subventricular Zone. Int J Mol Sci 2024; 25:2540. [PMID: 38473789 DOI: 10.3390/ijms25052540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 02/14/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
In the adult mammalian brain, neurons are produced from neural stem cells (NSCs) residing in two niches-the subventricular zone (SVZ), which forms the lining of the lateral ventricles, and the subgranular zone in the hippocampus. Epigenetic mechanisms contribute to maintaining distinct cell fates by suppressing gene expression that is required for deciding alternate cell fates. Several histone deacetylase (HDAC) inhibitors can affect adult neurogenesis in vivo. However, data regarding the role of specific HDACs in cell fate decisions remain limited. Herein, we demonstrate that HDAC8 participates in the regulation of the proliferation and differentiation of NSCs/neural progenitor cells (NPCs) in the adult mouse SVZ. Specific knockout of Hdac8 in NSCs/NPCs inhibited proliferation and neural differentiation. Treatment with the selective HDAC8 inhibitor PCI-34051 reduced the neurosphere size in cultures from the SVZ of adult mice. Further transcriptional datasets revealed that HDAC8 inhibition in adult SVZ cells disturbs biological processes, transcription factor networks, and key regulatory pathways. HDAC8 inhibition in adult SVZ neurospheres upregulated the cytokine-mediated signaling and downregulated the cell cycle pathway. In conclusion, HDAC8 participates in the regulation of in vivo proliferation and differentiation of NSCs/NPCs in the adult SVZ, which provides insights into the underlying molecular mechanisms.
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Affiliation(s)
- Momoko Fukuda
- Department of Anatomy and Developmental Biology, School of Medicine, Shimane University, 89-1, Enya-cho, Izumo-shi 693-8501, Japan
| | - Yuki Fujita
- Department of Anatomy and Developmental Biology, School of Medicine, Shimane University, 89-1, Enya-cho, Izumo-shi 693-8501, Japan
| | - Yuko Hino
- Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
| | - Mitsuyoshi Nakao
- Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
| | - Katsuhiko Shirahige
- Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
- Department of Cell and Molecular Biology, Karolinska Institutet, Biomedicum, Quarter A6, 171 77 Stockholm, Sweden
| | - Toshihide Yamashita
- Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita 565-0871, Japan
- WPI Immunology Frontier Research Center, Osaka University, 3-1, Yamadaoka, Suita 565-0871, Japan
- Graduate School of Frontier Biosciences, Osaka University, 1-3, Yamadaoka, Suita 565-0871, Japan
- Department of Neuro-Medical Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita 565-0871, Japan
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6
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Minotti C, Graziani L, Sallicandro E, Digilio MC, Falasca R, Alesi V, Novelli G, Dentici ML, Loddo S, Novelli A. Case report: A new de novo 6q21q22.1 interstitial deletion case in a girl with cerebellar vermis hypoplasia and developmental delay and literature review. Front Genet 2024; 14:1315291. [PMID: 38380230 PMCID: PMC10877002 DOI: 10.3389/fgene.2023.1315291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/04/2023] [Indexed: 02/22/2024] Open
Abstract
Interstitial deletions involving 6q chromosomal region are rare. Less than 30 patients have been described to date, and fewer have been characterized by high-resolution techniques, such as chromosomal microarray. Deletions involving 6q21q22.1 region are associated with an extremely wide and heterogeneous clinical spectrum, thus genotype-phenotype correlation based on the size of the rearranged region and on the involved genes is complex, even among individuals with overlapping deletions. Here we describe the phenotypic and molecular characterization of a new 6q interstitial deletion in a girl with developmental delay, intellectual disability, cerebellar vermis hypoplasia, facial peculiar characteristics, ataxia and ocular abnormalities. Microarray analysis of the proposita revealed a 7.9 Mb interstitial de novo deletion at 6q21q22.1 chromosomal region, which spanned from nucleotides 108,337,770 to 116,279,453 (GRCh38/hg38). The present case, alongside with a systematic review of the literature, provides further evidence that could aid to the definition of the Smallest Region of Overlap and of the genomic traits that are associated with particular phenotypes, focusing on neurological findings and especially on cerebellar anomalies.
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Affiliation(s)
- Chiara Minotti
- Medical Genetics Unit, Translational Pediatrics and Clinical Genetics Research Area, Bambino Gesù Children Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
- Medical Genetics Section, Depepartment of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy
| | - Ludovico Graziani
- Medical Genetics Unit, Translational Pediatrics and Clinical Genetics Research Area, Bambino Gesù Children Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
- Medical Genetics Section, Depepartment of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy
| | - Ester Sallicandro
- Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Maria Cristina Digilio
- Medical Genetics Unit, Translational Pediatrics and Clinical Genetics Research Area, Bambino Gesù Children Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Roberto Falasca
- Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Viola Alesi
- Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Giuseppe Novelli
- Medical Genetics Section, Depepartment of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy
- Medical Genetics Lab, Tor Vergata Hospital, Rome, Italy
| | - Maria Lisa Dentici
- Medical Genetics Unit, Translational Pediatrics and Clinical Genetics Research Area, Bambino Gesù Children Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
| | - Sara Loddo
- Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Antonio Novelli
- Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
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7
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Shi J, Wang Z, Wang Z, Shao G, Li X. Epigenetic regulation in adult neural stem cells. Front Cell Dev Biol 2024; 12:1331074. [PMID: 38357000 PMCID: PMC10864612 DOI: 10.3389/fcell.2024.1331074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 01/12/2024] [Indexed: 02/16/2024] Open
Abstract
Neural stem cells (NSCs) exhibit self-renewing and multipotential properties. Adult NSCs are located in two neurogenic regions of adult brain: the ventricular-subventricular zone (V-SVZ) of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Maintenance and differentiation of adult NSCs are regulated by both intrinsic and extrinsic signals that may be integrated through expression of some key factors in the adult NSCs. A number of transcription factors have been shown to play essential roles in transcriptional regulation of NSC cell fate transitions in the adult brain. Epigenetic regulators have also emerged as key players in regulation of NSCs, neural progenitor cells and their differentiated progeny via epigenetic modifications including DNA methylation, histone modifications, chromatin remodeling and RNA-mediated transcriptional regulation. This minireview is primarily focused on epigenetic regulations of adult NSCs during adult neurogenesis, in conjunction with transcriptional regulation in these processes.
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Affiliation(s)
- Jiajia Shi
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Zilin Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Zhijun Wang
- Zhenhai Lianhua Hospital, Ningbo City, Zhejiang, China
| | - Guofeng Shao
- Department of Cardiothoracic Surgery, Lihuili Hospital Affiliated to Ningbo University, Ningbo City, Zhejiang, China
| | - Xiajun Li
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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8
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Aleksandrova Y, Neganova M. Deciphering the Mysterious Relationship between the Cross-Pathogenetic Mechanisms of Neurodegenerative and Oncological Diseases. Int J Mol Sci 2023; 24:14766. [PMID: 37834214 PMCID: PMC10573395 DOI: 10.3390/ijms241914766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/22/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
The relationship between oncological pathologies and neurodegenerative disorders is extremely complex and is a topic of concern among a growing number of researchers around the world. In recent years, convincing scientific evidence has accumulated that indicates the contribution of a number of etiological factors and pathophysiological processes to the pathogenesis of these two fundamentally different diseases, thus demonstrating an intriguing relationship between oncology and neurodegeneration. In this review, we establish the general links between three intersecting aspects of oncological pathologies and neurodegenerative disorders, i.e., oxidative stress, epigenetic dysregulation, and metabolic dysfunction, examining each process in detail to establish an unusual epidemiological relationship. We also focus on reviewing the current trends in the research and the clinical application of the most promising chemical structures and therapeutic platforms that have a modulating effect on the above processes. Thus, our comprehensive analysis of the set of molecular determinants that have obvious cross-functional pathways in the pathogenesis of oncological and neurodegenerative diseases can help in the creation of advanced diagnostic tools and in the development of innovative pharmacological strategies.
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Affiliation(s)
- Yulia Aleksandrova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
| | - Margarita Neganova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Russia;
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 420088 Kazan, Russia
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9
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Park J, Lee K, Kim K, Yi SJ. The role of histone modifications: from neurodevelopment to neurodiseases. Signal Transduct Target Ther 2022; 7:217. [PMID: 35794091 PMCID: PMC9259618 DOI: 10.1038/s41392-022-01078-9] [Citation(s) in RCA: 130] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/11/2022] [Accepted: 06/21/2022] [Indexed: 12/24/2022] Open
Abstract
Epigenetic regulatory mechanisms, including DNA methylation, histone modification, chromatin remodeling, and microRNA expression, play critical roles in cell differentiation and organ development through spatial and temporal gene regulation. Neurogenesis is a sophisticated and complex process by which neural stem cells differentiate into specialized brain cell types at specific times and regions of the brain. A growing body of evidence suggests that epigenetic mechanisms, such as histone modifications, allow the fine-tuning and coordination of spatiotemporal gene expressions during neurogenesis. Aberrant histone modifications contribute to the development of neurodegenerative and neuropsychiatric diseases. Herein, recent progress in understanding histone modifications in regulating embryonic and adult neurogenesis is comprehensively reviewed. The histone modifications implicated in neurodegenerative and neuropsychiatric diseases are also covered, and future directions in this area are provided.
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Affiliation(s)
- Jisu Park
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyubin Lee
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyunghwan Kim
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
| | - Sun-Ju Yi
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
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10
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Srivastava A, Banerjee J, Dubey V, Tripathi M, Chandra PS, Sharma MC, Lalwani S, Siraj F, Doddamani R, Dixit AB. Role of Altered Expression, Activity and Sub-cellular Distribution of Various Histone Deacetylases (HDACs) in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis. Cell Mol Neurobiol 2022; 42:1049-1064. [PMID: 33258018 PMCID: PMC11441253 DOI: 10.1007/s10571-020-00994-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022]
Abstract
Histone deacetylases (HDACs) have been described to have both neurotoxic and neuroprotective roles, and partly, depend on its sub-cellular distribution. HDAC inhibitors have a long history of use in the treatment of various neurological disorders including epilepsy. Key role of HDACs in GABAergic neurotransmission, synaptogenesis, synaptic plasticity and memory formation was demonstrated whereas very less is known about their role in drug-resistant epilepsy pathologies. The present study was aimed to investigate the changes in the expression of HDACs, activity and its sub-cellular distribution in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) patients. For this study, surgically resected hippocampal tissue specimens of 28 MTLE-HS patients and 20 hippocampus from post-mortem cases were obtained. Real-time PCR was done to analyse the mRNA expression. HDAC activity and the protein levels of HDACs in cytoplasm as well as nucleus were measured spectrophotometrically. Further, sub-cellular localization of HDACs was characterized by immunofluorescence. Significant upregulation of HDAC1, HDAC2, HDAC4, HDAC5, HDAC6, HDAC10 and HDAC11 mRNA were observed in MTLE-HS. Alterations in the mRNA expression of glutamate and gamma-aminobutyric acid (GABA) receptor subunits have been also demonstrated. We observed significant increase of HDAC activity and nuclear level of HDAC1, HDAC2, HDAC5 and HDAC11 in the hippocampal samples obtained from patients with MTLE-HS. Moreover, we found altered cytoplasmic level of HDAC4, HDAC6 and HDAC10 in the hippocampal sample obtained from patients with MTLE-HS. Alterations in the level of HDACs could potentially be part of a dynamic transcription regulation associated with MTLE-HS. Changes in cytoplasmic level of HDAC4, 6 and 10 suggest that cytoplasmic substrates may play a crucial role in the pathophysiology of MTLE-HS. Knowledge regarding expression pattern and sub-cellular distribution of HDACs may help to devise specific HDACi therapy for epilepsy.
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Affiliation(s)
- Arpna Srivastava
- Centre of Excellence for Epilepsy, AIIMS, New Delhi, India
- Department of Neurosurgery, AIIMS, New Delhi, India
| | - Jyotirmoy Banerjee
- Centre of Excellence for Epilepsy, AIIMS, New Delhi, India
- Department of Biophysics, AIIMS, New Delhi, India
| | - Vivek Dubey
- Department of Biophysics, AIIMS, New Delhi, India
| | - Manjari Tripathi
- Centre of Excellence for Epilepsy, AIIMS, New Delhi, India
- Department of Neurology, AIIMS, New Delhi, India
| | - P Sarat Chandra
- Centre of Excellence for Epilepsy, AIIMS, New Delhi, India
- Department of Neurosurgery, AIIMS, New Delhi, India
| | - M C Sharma
- Department of Pathology, AIIMS, New Delhi, India
| | - Sanjeev Lalwani
- Department of Forensic Medicine and Toxicology, AIIMS, New Delhi, India
| | - Fouzia Siraj
- National Institute of Pathology, New Delhi, India
| | | | - Aparna Banerjee Dixit
- Centre of Excellence for Epilepsy, AIIMS, New Delhi, India.
- Dr B R Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi, India.
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11
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Nieto-Estevez V, Changarathil G, Adeyeye AO, Coppin MO, Kassim RS, Zhu J, Hsieh J. HDAC1 Regulates Neuronal Differentiation. Front Mol Neurosci 2022; 14:815808. [PMID: 35095417 PMCID: PMC8789757 DOI: 10.3389/fnmol.2021.815808] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/21/2021] [Indexed: 11/13/2022] Open
Abstract
In adult hippocampal neurogenesis, chromatin modification plays an important role in neural stem cell self-renewal and differentiation by regulating the expression of multiple genes. Histone deacetylases (HDACs), which remove acetyl groups from histones, create a non-permissive chromatin that prevents transcription of genes involved in adult neurogenesis. HDAC inhibitors have been shown to promote adult neurogenesis and have also been used to treat nervous system disorders, such as epilepsy. However, most HDAC inhibitors are not specific and may have other targets. Therefore, it is important to decipher the role of individual HDACs in adult hippocampal neurogenesis. HDACs 1, 2, and 3 have been found expressed at different cellular stages during neurogenesis. Conditional deletion of HDAC2 in neural stem cells impairs neuronal differentiation in adult hippocampus. HDAC3 supports proliferation of adult hippocampal neural stem/progenitor cells. The role of HDAC1 in adult neurogenesis remains still open. Here, we used a conditional knock-out mouse to block HDAC1 expression in neural stem cells (Nestin+ cells) during hippocampal neurogenesis. Our results showed that both HDAC1 and HDAC2 are expressed in all cellular stages during hippocampal neurogenesis. Moreover, we found that deletion of HDAC1 by viral infection of neural stem cells is sufficient to compromise neuronal differentiation in vitro. However, we were unable to reduce the expression of HDAC1 in vivo using Nestin-CreERT2 mice. Understanding the role of HDAC1 may lead to ways to control stem cell proliferation and neuronal regeneration in the adult hippocampus, and to more specific HDAC therapeutics for neurological disorders.
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Affiliation(s)
- Vanesa Nieto-Estevez
- Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX, United States
- Brain Health Consortium, The University of Texas at San Antonio, San Antonio, TX, United States
| | - Gopakumar Changarathil
- Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX, United States
- Brain Health Consortium, The University of Texas at San Antonio, San Antonio, TX, United States
| | - Adebayo Olukayode Adeyeye
- Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX, United States
- Brain Health Consortium, The University of Texas at San Antonio, San Antonio, TX, United States
| | - Marissa Olga Coppin
- Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX, United States
- Brain Health Consortium, The University of Texas at San Antonio, San Antonio, TX, United States
| | - Rawan Serena Kassim
- Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX, United States
- Brain Health Consortium, The University of Texas at San Antonio, San Antonio, TX, United States
| | - Jingfei Zhu
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States
| | - Jenny Hsieh
- Department of Neuroscience, Developmental and Regenerative Biology, The University of Texas at San Antonio, San Antonio, TX, United States
- Brain Health Consortium, The University of Texas at San Antonio, San Antonio, TX, United States
- *Correspondence: Jenny Hsieh,
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12
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Tay EXY, Chia K, Ong DST. Epigenetic plasticity and redox regulation of neural stem cell state and fate. Free Radic Biol Med 2021; 170:116-130. [PMID: 33684459 DOI: 10.1016/j.freeradbiomed.2021.02.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 01/20/2021] [Accepted: 02/24/2021] [Indexed: 12/16/2022]
Abstract
The neural stem cells (NSCs) are essential for normal brain development and homeostasis. The cell state (i.e. quiescent versus activated) and fate (i.e. the cell lineage of choice upon differentiation) of NSCs are tightly controlled by various redox and epigenetic regulatory mechanisms. There is an increasing appreciation that redox and epigenetic regulations are intimately linked, but how this redox-epigenetics crosstalk affects NSC activity remains poorly understood. Another unresolved topic is whether the NSCs actually contribute to brain ageing and neurodegenerative diseases. In this review, we aim to 1) distill concepts that underlie redox and epigenetic regulation of NSC state and fate; 2) provide examples of the redox-epigenetics crosstalk in NSC biology; and 3) highlight potential redox- and epigenetic-based therapeutic opportunities to rescue NSC dysfunctions in ageing and neurodegenerative diseases.
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Affiliation(s)
- Emmy Xue Yun Tay
- Department of Physiology, National University of Singapore, Singapore, 117593, Singapore
| | - Kimberly Chia
- Department of Physiology, National University of Singapore, Singapore, 117593, Singapore
| | - Derrick Sek Tong Ong
- Department of Physiology, National University of Singapore, Singapore, 117593, Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore; National Neuroscience Institute, Singapore, 308433, Singapore.
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13
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Frankowski H, Yeboah F, Berry BJ, Kinoshita C, Lee M, Evitts K, Davis J, Kinoshita Y, Morrison RS, Young JE. Knock-Down of HDAC2 in Human Induced Pluripotent Stem Cell Derived Neurons Improves Neuronal Mitochondrial Dynamics, Neuronal Maturation and Reduces Amyloid Beta Peptides. Int J Mol Sci 2021; 22:ijms22052526. [PMID: 33802405 PMCID: PMC7959288 DOI: 10.3390/ijms22052526] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/28/2021] [Accepted: 02/28/2021] [Indexed: 02/06/2023] Open
Abstract
Histone deacetylase 2 (HDAC2) is a major HDAC protein in the adult brain and has been shown to regulate many neuronal genes. The aberrant expression of HDAC2 and subsequent dysregulation of neuronal gene expression is implicated in neurodegeneration and brain aging. Human induced pluripotent stem cell-derived neurons (hiPSC-Ns) are widely used models for studying neurodegenerative disease mechanisms, but the role of HDAC2 in hiPSC-N differentiation and maturation has not been explored. In this study, we show that levels of HDAC2 progressively decrease as hiPSCs are differentiated towards neurons. This suppression of HDAC2 inversely corresponds to an increase in neuron-specific isoforms of Endophilin-B1, a multifunctional protein involved in mitochondrial dynamics. Expression of neuron-specific isoforms of Endophilin-B1 is accompanied by concomitant expression of a neuron-specific alternative splicing factor, SRRM4. Manipulation of HDAC2 and Endophilin-B1 using lentiviral approaches shows that the knock-down of HDAC2 or the overexpression of a neuron-specific Endophilin-B1 isoform promotes mitochondrial elongation and protects against cytotoxic stress in hiPSC-Ns, while HDAC2 knock-down specifically influences genes regulating mitochondrial dynamics and synaptogenesis. Furthermore, HDAC2 knock-down promotes enhanced mitochondrial respiration and reduces levels of neurotoxic amyloid beta peptides. Collectively, our study demonstrates a role for HDAC2 in hiPSC-neuronal differentiation, highlights neuron-specific isoforms of Endophilin-B1 as a marker of differentiating hiPSC-Ns and demonstrates that HDAC2 regulates key neuronal and mitochondrial pathways in hiPSC-Ns.
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Affiliation(s)
- Harald Frankowski
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; (H.F.); (F.Y.); (B.J.B.); (C.K.); (M.L.); (K.E.); (J.D.); (Y.K.)
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
| | - Fred Yeboah
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; (H.F.); (F.Y.); (B.J.B.); (C.K.); (M.L.); (K.E.); (J.D.); (Y.K.)
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
- Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA
| | - Bonnie J. Berry
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; (H.F.); (F.Y.); (B.J.B.); (C.K.); (M.L.); (K.E.); (J.D.); (Y.K.)
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
| | - Chizuru Kinoshita
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; (H.F.); (F.Y.); (B.J.B.); (C.K.); (M.L.); (K.E.); (J.D.); (Y.K.)
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
| | - Michelle Lee
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; (H.F.); (F.Y.); (B.J.B.); (C.K.); (M.L.); (K.E.); (J.D.); (Y.K.)
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
| | - Kira Evitts
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; (H.F.); (F.Y.); (B.J.B.); (C.K.); (M.L.); (K.E.); (J.D.); (Y.K.)
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
| | - Joshua Davis
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; (H.F.); (F.Y.); (B.J.B.); (C.K.); (M.L.); (K.E.); (J.D.); (Y.K.)
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
| | - Yoshito Kinoshita
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; (H.F.); (F.Y.); (B.J.B.); (C.K.); (M.L.); (K.E.); (J.D.); (Y.K.)
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
| | - Richard S. Morrison
- Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA;
| | - Jessica E. Young
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; (H.F.); (F.Y.); (B.J.B.); (C.K.); (M.L.); (K.E.); (J.D.); (Y.K.)
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
- Correspondence:
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14
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The transcriptome of anterior regeneration in earthworm Eudrilus eugeniae. Mol Biol Rep 2020; 48:259-283. [PMID: 33306150 DOI: 10.1007/s11033-020-06044-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 11/28/2020] [Indexed: 12/25/2022]
Abstract
The oligochaete earthworm, Eudrilus eugeniae is capable of regenerating both anterior and posterior segments. The present study focuses on the transcriptome analysis of earthworm E. eugeniae to identify and functionally annotate the key genes supporting the anterior blastema formation and regulating the anterior regeneration of the worm. The Illumina sequencing generated a total of 91,593,182 raw reads which were assembled into 105,193 contigs using CLC genomics workbench. In total, 40,946 contigs were annotated against the NCBI nr and SwissProt database and among them, 15,702 contigs were assigned to 14,575 GO terms. Besides a total of 9389 contigs were mapped to 416 KEGG biological pathways. The RNA-Seq comparison study identified 10,868 differentially expressed genes (DEGs) and of them, 3986 genes were significantly upregulated in the anterior regenerated blastema tissue samples of the worm. The GO enrichment analysis showed angiogenesis and unfolded protein binding as the top enriched functions and the pathway enrichment analysis denoted TCA cycle as the most significantly enriched pathway associated with the upregulated gene dataset of the worm. The identified DEGs and their function and pathway information can be effectively utilized further to interpret the key cellular, genetic and molecular events associated with the regeneration of the worm.
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15
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Maitra S, Khandelwal N, Kootar S, Sant P, Pathak SS, Reddy S, K. AP, Murty US, Chakravarty S, Kumar A. Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders. Brain Sci 2020; 10:brainsci10110833. [PMID: 33182385 PMCID: PMC7695311 DOI: 10.3390/brainsci10110833] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 12/13/2022] Open
Abstract
Depression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their etiopathology. In addition to the well-studied genetic component, research in the past two decades has implicated diverse epigenetic mechanisms in mediating the negative effects of chronic stressful events on neural circuits. This includes the cognitive circuitry, where the dynamic hippocampal dentate gyrus (DG) neurogenesis gets affected in depression and related affective disorders. Most of these epigenetic studies have focused on the impact of acetylation/deacetylation and methylation of several histone lysine residues on neural gene expression. However, there is a dearth of investigation into the role of demethylation of these lysine residues in chronic stress-induced changes in neurogenesis that results in altered behaviour. Here, using the chronic social defeat stress (CSDS) paradigm to induce depression and anxiety in C57BL/6 mice and ex vivo DG neural stem/progenitor cell (NSCs/NPCs) culture we show the role of the members of the JMJD2/KDM4 family of histone lysine demethylases (KDMs) in mediating stress-induced changes in DG neurogenesis and mood disorders. The study suggests a critical role of JMJD2D in DG neurogenesis. Altered enrichment of JMJD2D on the promoters of Id2 (inhibitor of differentiation 2) and Sox2 (SRY-Box Transcription Factor 2) was observed during proliferation and differentiation of NSCs/NPCs obtained from the DG. This would affect the demethylation of repressive epigenetic mark H3K9, thus activating or repressing these and possibly other genes involved in regulating proliferation and differentiation of DG NSCs/NPCs. Treatment of the NSCs/NPCs culture with Dimethyloxallyl Glycine (DMOG), an inhibitor of JMJDs, led to attenuation in their proliferation capacity. Additionally, systemic administration of DMOG in mice for 10 days induced depression-like and anxiety-like phenotype without any stress exposure.
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Affiliation(s)
- Swati Maitra
- Applied Biology, CSIR—Indian Institute of Chemical Technology (IICT), Uppal Road, Tarnaka, Hyderabad 500007, Telangana, India; (S.M.); (U.S.M.)
| | - Nitin Khandelwal
- Epigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, India; (N.K.); (S.K.); (P.S.); (S.S.P.); (S.R.); (A.P.K.)
| | - Scherazad Kootar
- Epigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, India; (N.K.); (S.K.); (P.S.); (S.S.P.); (S.R.); (A.P.K.)
| | - Pooja Sant
- Epigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, India; (N.K.); (S.K.); (P.S.); (S.S.P.); (S.R.); (A.P.K.)
| | - Salil S. Pathak
- Epigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, India; (N.K.); (S.K.); (P.S.); (S.S.P.); (S.R.); (A.P.K.)
| | - Sujatha Reddy
- Epigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, India; (N.K.); (S.K.); (P.S.); (S.S.P.); (S.R.); (A.P.K.)
| | - Annapoorna P. K.
- Epigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, India; (N.K.); (S.K.); (P.S.); (S.S.P.); (S.R.); (A.P.K.)
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
| | - Upadhyayula Suryanarayana Murty
- Applied Biology, CSIR—Indian Institute of Chemical Technology (IICT), Uppal Road, Tarnaka, Hyderabad 500007, Telangana, India; (S.M.); (U.S.M.)
- National Institute of Pharmaceutical Education and Research (NIPER), Guwahati 781101, Assam, India
| | - Sumana Chakravarty
- Applied Biology, CSIR—Indian Institute of Chemical Technology (IICT), Uppal Road, Tarnaka, Hyderabad 500007, Telangana, India; (S.M.); (U.S.M.)
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
- Correspondence: (S.C.); (A.K.)
| | - Arvind Kumar
- Epigenetics & Neuropsychiatric Disorders Laboratory, CSIR—Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Habsiguda, Hyderabad 500007, Telangana, India; (N.K.); (S.K.); (P.S.); (S.S.P.); (S.R.); (A.P.K.)
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, Uttar Pradesh, India
- Correspondence: (S.C.); (A.K.)
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16
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Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability. Genes (Basel) 2020; 11:genes11050556. [PMID: 32429325 PMCID: PMC7288346 DOI: 10.3390/genes11050556] [Citation(s) in RCA: 225] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/08/2020] [Accepted: 05/11/2020] [Indexed: 02/06/2023] Open
Abstract
Histone deacetylases (HDACs) are evolutionary conserved enzymes which operate by removing acetyl groups from histones and other protein regulatory factors, with functional consequences on chromatin remodeling and gene expression profiles. We provide here a review on the recent knowledge accrued on the zinc-dependent HDAC protein family across different species, tissues, and human pathologies, specifically focusing on the role of HDAC inhibitors as anti-cancer agents. We will investigate the chemical specificity of different HDACs and discuss their role in the human interactome as members of chromatin-binding and regulatory complexes.
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17
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Pharmacological intervention of histone deacetylase enzymes in the neurodegenerative disorders. Life Sci 2020; 243:117278. [PMID: 31926248 DOI: 10.1016/j.lfs.2020.117278] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 12/31/2019] [Accepted: 01/01/2020] [Indexed: 02/06/2023]
Abstract
Reversal of aging symptoms and related disorders are the challenging task where epigenetic is a crucial player that includes DNA methylation, histone modification; chromatin remodeling and regulation that are linked to the progression of various neurodegenerative disorders (NDDs). Overexpression of various histone deacetylase (HDACs) can activate Glycogen synthase kinase 3 which promotes the hyperphosphorylation of tau and inhibits its degradation. While HDAC is important for maintaining the neuronal morphology and brain homeostasis, at the same time, these enzymes are promoting neurodegeneration, if it is deregulated. Different experimental models have also confirmed the neuroprotective effects caused by HDAC enzymes through the regulation of neuronal apoptosis, inflammatory response, DNA damage, cell cycle regulation, and metabolic dysfunction. Apart from transcriptional regulation, protein-protein interaction, histone post-translational modifications, deacetylation mechanism of non-histone protein and direct association with disease proteins have been linked to neuronal imbalance. Histone deacetylases inhibitors (HDACi) can be able to alter gene expression and shown its efficacy on experimental models, and in clinical trials for NDD's and found to be a very promising therapeutic agent with certain limitation, for instance, non-specific target effect, isoform-selectivity, specificity, and limited number of predicted biomarkers. Herein, we discussed (i) the catalytic mechanism of the deacetylation process of various HDAC's in in vivo and in vitro experimental models, (ii) how HDACs are participating in neuroprotection as well as in neurodegeneration, (iii) a comprehensive role of HDACi in maintaining neuronal homeostasis and (iv) therapeutic role of biomolecules to modulate HDACs.
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18
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Abstract
Biomarker discovery and validation are necessary for improving the prediction of clinical outcomes and patient monitoring. Despite considerable interest in biomarker discovery and development, improvements in the range and quality of biomarkers are still needed. The main challenge is how to integrate preclinical data to obtain a reliable biomarker that can be measured with acceptable costs in routine clinical practice. Epigenetic alterations are already being incorporated as valuable candidates in the biomarker field. Furthermore, their reversible nature offers a promising opportunity to ameliorate disease symptoms by using epigenetic-based therapy. Thus, beyond helping to understand disease biology, clinical epigenetics is being incorporated into patient management in oncology, as well as being explored for clinical applicability for other human pathologies such as neurological and infectious diseases and immune system disorders.
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Lawlor L, Yang XB. Harnessing the HDAC-histone deacetylase enzymes, inhibitors and how these can be utilised in tissue engineering. Int J Oral Sci 2019; 11:20. [PMID: 31201303 PMCID: PMC6572769 DOI: 10.1038/s41368-019-0053-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 05/02/2019] [Accepted: 05/05/2019] [Indexed: 02/07/2023] Open
Abstract
There are large knowledge gaps regarding how to control stem cells growth and differentiation. The limitations of currently available technologies, such as growth factors and/or gene therapies has led to the search of alternatives. We explore here how a cell's epigenome influences determination of cell type, and potential applications in tissue engineering. A prevalent epigenetic modification is the acetylation of DNA core histone proteins. Acetylation levels heavily influence gene transcription. Histone deacetylase (HDAC) enzymes can remove these acetyl groups, leading to the formation of a condensed and more transcriptionally silenced chromatin. Histone deacetylase inhibitors (HDACis) can inhibit these enzymes, resulting in the increased acetylation of histones, thereby affecting gene expression. There is strong evidence to suggest that HDACis can be utilised in stem cell therapies and tissue engineering, potentially providing novel tools to control stem cell fate. This review introduces the structure/function of HDAC enzymes and their links to different tissue types (specifically bone, cardiac, neural tissues), including the history, current status and future perspectives of using HDACis for stem cell research and tissue engineering, with particular attention paid to how different HDAC isoforms may be integral to this field.
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Affiliation(s)
- Liam Lawlor
- Department of Oral Biology, University of Leeds, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK
- Doctoral Training Centre in Tissue Engineering and Regenerative Medicine, Institute of Medical and Biological Engineering, School of Mechanical Engineering, University of Leeds, Leeds, UK
| | - Xuebin B Yang
- Department of Oral Biology, University of Leeds, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, LS9 7TF, UK.
- Doctoral Training Centre in Tissue Engineering and Regenerative Medicine, Institute of Medical and Biological Engineering, School of Mechanical Engineering, University of Leeds, Leeds, UK.
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20
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De Simone A, Milelli A. Histone Deacetylase Inhibitors as Multitarget Ligands: New Players in Alzheimer's Disease Drug Discovery? ChemMedChem 2019; 14:1067-1073. [PMID: 30958639 DOI: 10.1002/cmdc.201900174] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Indexed: 01/14/2023]
Abstract
Histone deacetylase inhibitors (HDACIs) are responsible for controlling gene expression by modulating the acetylation status of histone proteins. Furthermore, they modulate the activity of cytoplasmic non-histone proteins. Due to the involvement of HDACs in neurodevelopment, memory formation, and cognitive processes, HDACIs have been suggested as innovative agents for the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). Given their mechanisms of action and the complex nature of AD, HDACIs have been proposed for the design of novel multitarget ligands (MTLs). To this aim, the fragment responsible for HDAC inhibition has been coupled with other structures that are able to provide additional biological actions, such as antioxidant activity or the inhibition of phosphodiesterase 5, transglutaminase 2, and glycogen synthase kinase 3β. Herein we discuss recent efforts to design HDACI-based MTLs as potential disease-modifying entities.
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Affiliation(s)
- Angela De Simone
- Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso D'Augusto 237, 47921, Rimini, Italy
| | - Andrea Milelli
- Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso D'Augusto 237, 47921, Rimini, Italy
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21
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The role of adult hippocampal neurogenesis in brain health and disease. Mol Psychiatry 2019; 24:67-87. [PMID: 29679070 PMCID: PMC6195869 DOI: 10.1038/s41380-018-0036-2] [Citation(s) in RCA: 428] [Impact Index Per Article: 71.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 01/15/2018] [Accepted: 01/31/2018] [Indexed: 12/18/2022]
Abstract
Adult neurogenesis in the dentate gyrus of the hippocampus is highly regulated by a number of environmental and cell-intrinsic factors to adapt to environmental changes. Accumulating evidence suggests that adult-born neurons may play distinct physiological roles in hippocampus-dependent functions, such as memory encoding and mood regulation. In addition, several brain diseases, such as neurological diseases and mood disorders, have deleterious effects on adult hippocampal neurogenesis, and some symptoms of those diseases can be partially explained by the dysregulation of adult hippocampal neurogenesis. Here we review a possible link between the physiological functions of adult-born neurons and their roles in pathological conditions.
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22
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Liao L, Wang X, Yao X, Zhang B, Zhou L, Huang J. Gestational stress induced differential expression of HDAC2 in male rat offspring hippocampus during development. Neurosci Res 2018; 147:9-16. [PMID: 30452948 DOI: 10.1016/j.neures.2018.11.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 10/11/2018] [Accepted: 11/15/2018] [Indexed: 10/27/2022]
Abstract
Accumulating evidence from preclinical and clinical studies indicates prenatal exposure to stress or excess glucocorticoids can affect offspring brain. HDAC2 is an important target of glucocorticoid. Here we detected HDAC2 expression in male offspring hippocampus from gestational restraint stressed rat during development and the relationship between HDAC2 expression and behaviors and neurogenesis in male offspring. Pregnant rats received restrained stress during the last week of pregnancy. Expressions of HDAC2 in offspring hippocampus were detected on postnatal 0 day (P0) and 60 days (P60). Neurogenesis was evaluated by Doublecortin (DCX) staining on P60. Anxiety-like behavior and cognition were detected in open field, elevated plus maze, novel object recognition test, and Barnes maze. We found that HDAC2 expression in the hippocampus of male prenatally stressed offspring (MPSO) was similar to the male control offspring on P0, but significantly lower on P60. Corresponding to the decreased expression of HDAC2 in MPSO hippocampus at P60, neurogenesis in the dentate gyrus of MPSO was significantly lower than the control male offspring. And MPSO also showed greater anxiety and poorer learning and memories abilities than control male offspring. These showed that HDAC2 could partly explain the effects of gestational stress on male offspring behaviors.
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Affiliation(s)
- Libin Liao
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, PR China; Department of Histology and Embryology, Basic Medical College of Xinjiang Medical University, Ürümqi, Xinjiang, PR China
| | - Xueqin Wang
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Xueping Yao
- Department of Mechanism Lab Centre, Basic Medical College of Xinjiang Medical University, Ürümqi, Xinjiang, PR China
| | - Bin Zhang
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, PR China
| | - Lihong Zhou
- Department of Human Anatomy, School of Medicine, Hunan Normal University, Changsha, Hunan, PR China.
| | - Jufang Huang
- Department of Anatomy and Neurobiology, Central South University School of Basic Medical Sciences, Changsha, Hunan, PR China.
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Saha A, Tiwari S, Dharmarajan S, Otteson DC, Belecky-Adams TL. Class I histone deacetylases in retinal progenitors and differentiating ganglion cells. Gene Expr Patterns 2018; 30:37-48. [PMID: 30179675 DOI: 10.1016/j.gep.2018.08.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/28/2018] [Accepted: 08/31/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND The acetylation state of histones has been used as an indicator of the developmental state of progenitor and differentiating cells. The goal of this study was to determine the nuclear localization patterns of Class I histone deacetylases (HDACs) in retinal progenitor cells (RPCs) and retinal ganglion cells (RGCs), as the first step in understanding their potential importance in cell fate determination within the murine retina. RESULTS The only HDAC to label RPC nuclei at E16 and P5 was HDAC1. In contrast, there was generally increased nuclear localization of all Class I HDACs in differentiating RGCs. Between P5 and P30, SOX2 expression becomes restricted to Müller glial, cholinergic amacrine cells, and retinal astrocytes. Cholinergic amacrine showed a combination of changes in nuclear localization of Class I HDACs. Strikingly, although Müller glia and retinal astrocytes express many of the same genes, P30 Müller glial cells showed nuclear localization only of HDAC1, while retinal astrocytes were positive for HDACs 1, 2, and 3. CONCLUSION These results indicate there may be a role for one or more of the Class I HDACs in retinal cell type-specific differentiation.
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Affiliation(s)
- Ankita Saha
- Department of Biology, Indiana University-Purdue University Indianapolis, 723 W Michigan St, Indianapolis, IN, 46202, USA; Center for Developmental and Regenerative Biology, Indiana University- Purdue University Indianapolis, 723 W Michigan St, Indianapolis, IN, 46202, USA.
| | - Sarika Tiwari
- Department of Biology, Indiana University-Purdue University Indianapolis, 723 W Michigan St, Indianapolis, IN, 46202, USA; Center for Developmental and Regenerative Biology, Indiana University- Purdue University Indianapolis, 723 W Michigan St, Indianapolis, IN, 46202, USA.
| | - Subramanian Dharmarajan
- Department of Biology, Indiana University-Purdue University Indianapolis, 723 W Michigan St, Indianapolis, IN, 46202, USA; Center for Developmental and Regenerative Biology, Indiana University- Purdue University Indianapolis, 723 W Michigan St, Indianapolis, IN, 46202, USA.
| | - Deborah C Otteson
- University of Houston College of Optometry, 4901 Calhoun Rd. Rm 2195, Houston, TX, 77204-2020, USA.
| | - Teri L Belecky-Adams
- Department of Biology, Indiana University-Purdue University Indianapolis, 723 W Michigan St, Indianapolis, IN, 46202, USA; Center for Developmental and Regenerative Biology, Indiana University- Purdue University Indianapolis, 723 W Michigan St, Indianapolis, IN, 46202, USA.
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24
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Wang SE, Ko SY, Kim YS, Jo S, Lee SH, Jung SJ, Son H. Capsaicin upregulates HDAC2 via TRPV1 and impairs neuronal maturation in mice. Exp Mol Med 2018. [PMID: 29520110 PMCID: PMC5898893 DOI: 10.1038/emm.2017.289] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Transient receptor potential vanilloid 1 (TRPV1) affects mood and neuroplasticity in the brain, where its role is poorly understood. In the present study we investigated whether capsaicin (8-methyl-N-vanillyl-trans-6-nonenamide), an agonist of TRPV1, induced chromatin remodeling and thereby altered gene expression related to synaptic plasticity. We found that capsaicin treatment resulted in upregulation of histone deacetylase 2 (HDAC2) in the mouse hippocampus and HDAC2 was enriched at Psd95, synaptophysin, GLUR1, GLUR2 promoters. Viral-mediated hippocampal knockdown of HDAC2 induced expression of Synapsin I and prevented the detrimental effects of capsaicin on Synapsin I expression in mice, supporting the role of HDAC2 in regulation of capsaicin-induced Synapsin I expression. Taken together, our findings implicate HDAC2 in capsaicin-induced transcriptional regulation of synaptic molecules and support the view that HDAC2 is a molecular link between TRPV1 activity and synaptic plasticity.
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Affiliation(s)
- Sung Eun Wang
- Graduate School of Biomedical Science and Engineering, Hanyang Biomedical Research Institute, College of Medicine, Hanyang University, Seongdong-gu, Seoul, Republic of Korea
| | - Seung Yeon Ko
- Graduate School of Biomedical Science and Engineering, Hanyang Biomedical Research Institute, College of Medicine, Hanyang University, Seongdong-gu, Seoul, Republic of Korea
| | - Yong-Seok Kim
- Graduate School of Biomedical Science and Engineering, Hanyang Biomedical Research Institute, College of Medicine, Hanyang University, Seongdong-gu, Seoul, Republic of Korea.,Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seongdong-gu, Seoul, Republic of Korea
| | - Sungsin Jo
- Hanyang University Hospital for Rheumatic Disease, Hanyang University, Seongdong-gu, Seoul, Republic of Korea
| | - Seung Hoon Lee
- Graduate School of Biomedical Science and Engineering, Hanyang Biomedical Research Institute, College of Medicine, Hanyang University, Seongdong-gu, Seoul, Republic of Korea
| | - Sung Jun Jung
- Graduate School of Biomedical Science and Engineering, Hanyang Biomedical Research Institute, College of Medicine, Hanyang University, Seongdong-gu, Seoul, Republic of Korea.,Department of Physiology, College of Medicine, Hanyang University, Seongdong-gu, Seoul, Republic of Korea
| | - Hyeon Son
- Graduate School of Biomedical Science and Engineering, Hanyang Biomedical Research Institute, College of Medicine, Hanyang University, Seongdong-gu, Seoul, Republic of Korea.,Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seongdong-gu, Seoul, Republic of Korea
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25
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Demyanenko S, Neginskaya M, Berezhnaya E. Expression of Class I Histone Deacetylases in Ipsilateral and Contralateral Hemispheres after the Focal Photothrombotic Infarction in the Mouse Brain. Transl Stroke Res 2017; 9:471-483. [PMID: 29218547 DOI: 10.1007/s12975-017-0595-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 11/27/2017] [Accepted: 11/28/2017] [Indexed: 12/19/2022]
Abstract
Histone acetylation and deacetylation are among the most important epigenetic processes that regulate gene expression. Nonselective inhibitors of histone deacetylases (HDAC) can protect brain cells during ischemia and stroke. However, which HDAC isoform is involved in this effect is unknown. Some isoforms of histone deacetylases (HDACs) protect brain cells after ischemia, whereas others can promote their death. Most studies consider early periods (1-24 h) after stroke, whereas little is known on the involvement of HDACs during recovery after stroke. In this study, cellular and intracellular rearrangement of class I HDACs (HDAC1, HDAC2, HDAC3, HDAC8) was investigated at late periods after photothrombotic infarction (PTI) of the mouse sensorimotor cortex in intact tissue that surrounds the ischemia core, in the corresponding region of the contralateral hemisphere, and in the hippocampus. Each HDAC isoform had a specific pattern of expression and intracellular distribution in neurons and astrocytes at different periods after the ischemia. We did not observe ischemia-induced changes in the subcellular localization of HDACs under study. Three days after the PTI, the expression of HDAC2 was increased in neurons of the damaged hemisphere. The activity of HDAC2 and HDAC8 was elevated 7 days after the ischemia both in neurons and astrocytes of the studied brain structures; the activity of HDAC8 was also increased 14 days after the ischemia. It is notable that the expression of class I HDACs in the intact hemisphere changes in the same way as their expression in the living tissue of the damaged hemisphere. HDAC1 was found both in the nuclei and cytoplasm of the brain cells; HDAC2 was predominantly localized in the nuclei, and HDAC8 was predominantly observed in the cytoplasm. This in addition to the regulation of gene transcription indicates nontranscriptional activity of HDAC1 and HDAC8 during recovery of the brain tissue after the ischemia. HDAC2 and HDAC8 were identified as potential mediators in an early recovery period after stroke, suggesting that selective inhibitors and activators of HDACs can be considered for therapeutic approaches in this period.
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Affiliation(s)
- Svetlana Demyanenko
- Laboratory of Molecular Neurobiology, Academy of Biology and Biotechnology, Southern Federal University, prospect Stachki 194/1, Rostov-on-Don, 344090, Russia.
| | - Maria Neginskaya
- Laboratory of Molecular Neurobiology, Academy of Biology and Biotechnology, Southern Federal University, prospect Stachki 194/1, Rostov-on-Don, 344090, Russia
| | - Elena Berezhnaya
- Laboratory of Molecular Neurobiology, Academy of Biology and Biotechnology, Southern Federal University, prospect Stachki 194/1, Rostov-on-Don, 344090, Russia
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26
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Review: adult neurogenesis contributes to hippocampal plasticity. Cell Tissue Res 2017; 373:693-709. [PMID: 29185071 DOI: 10.1007/s00441-017-2735-4] [Citation(s) in RCA: 174] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 10/27/2017] [Indexed: 12/18/2022]
Abstract
Adult hippocampal neurogenesis is the process by which new functional neurons are added to the adult dentate gyrus of the hippocampus. Animal studies have shown that the degree of adult hippocampal neurogenesis is regulated by local environmental cues as well as neural network activities. Furthermore, accumulating evidence has suggested that adult hippocampal neurogenesis plays prominent roles in hippocampus-dependent brain functions. In this review, we summarize the mechanisms underlying the regulation of adult hippocampal neurogenesis at various developmental stages and propose how adult-born neurons contribute to structural and functional hippocampal plasticity.
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27
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Morris G, Walder K, Carvalho AF, Tye SJ, Lucas K, Berk M, Maes M. The role of hypernitrosylation in the pathogenesis and pathophysiology of neuroprogressive diseases. Neurosci Biobehav Rev 2017; 84:453-469. [PMID: 28789902 DOI: 10.1016/j.neubiorev.2017.07.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 07/02/2017] [Accepted: 07/31/2017] [Indexed: 12/12/2022]
Abstract
There is a wealth of data indicating that de novo protein S-nitrosylation in general and protein transnitrosylation in particular mediates the bulk of nitric oxide signalling. These processes enable redox sensing and facilitate homeostatic regulation of redox dependent protein signalling, function, stability and trafficking. Increased S-nitrosylation in an environment of increasing oxidative and nitrosative stress (O&NS) is initially a protective mechanism aimed at maintaining protein structure and function. When O&NS becomes severe, mechanisms governing denitrosylation and transnitrosylation break down leading to the pathological state referred to as hypernitrosylation (HN). Such a state has been implicated in the pathogenesis and pathophysiology of several neuropsychiatric and neurodegenerative diseases and we investigate its potential role in the development and maintenance of neuroprogressive disorders. In this paper, we propose a model whereby the hypernitrosylation of a range of functional proteins and enzymes lead to changes in activity which conspire to produce at least some of the core abnormalities contributing to the development and maintenance of pathology in these illnesses.
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Affiliation(s)
- Gerwyn Morris
- Tir Na Nog, Bryn Road seaside 87, Llanelli, SA152LW, Wales, United Kingdom
| | - Ken Walder
- Deakin University, The Centre for Molecular and Medical Research, School of Medicine, P.O. Box 291, Geelong, 3220, Australia
| | - André F Carvalho
- Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, 60430-040, Fortaleza, CE, Brazil
| | - Susannah J Tye
- Deakin University, The Centre for Molecular and Medical Research, School of Medicine, P.O. Box 291, Geelong, 3220, Australia; Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, 60430-040, Fortaleza, CE, Brazil; Deakin University, IMPACT Strategic Research Centre, School of Medicine, P.O. Box 281, Geelong, 3220, Australia; Orygen Youth Health Research Centre and the Centre of Youth Mental Health, The Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, University of Melbourne, Parkville, 3052, Australia
| | - Kurt Lucas
- Multiphase Chemistry Department, Max Planck Institute for Chemistry, 55128 Mainz, Germany
| | - Michael Berk
- Deakin University, IMPACT Strategic Research Centre, School of Medicine, P.O. Box 281, Geelong, 3220, Australia; Orygen Youth Health Research Centre and the Centre of Youth Mental Health, The Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, University of Melbourne, Parkville, 3052, Australia.
| | - Michael Maes
- Deakin University, IMPACT Strategic Research Centre, School of Medicine, P.O. Box 281, Geelong, 3220, Australia; Department of Psychiatry, Chulalongkorn University, Faculty of Medicine, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
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28
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Delgado-Morales R, Agís-Balboa RC, Esteller M, Berdasco M. Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders. Clin Epigenetics 2017; 9:67. [PMID: 28670349 PMCID: PMC5493012 DOI: 10.1186/s13148-017-0365-z] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 06/11/2017] [Indexed: 12/26/2022] Open
Abstract
Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ameliorate neural decline during normal ageing and especially in neurological disorders. We will firstly discuss recent progress that supports a key role of epigenetic regulation during healthy ageing with an emphasis on the role of epigenetic regulation in adult neurogenesis. Then, we will focus on epigenetic alterations associated with ageing-related human disorders of the central nervous system. We will discuss examples in the context of psychiatric disorders, including schizophrenia and posttraumatic stress disorders, and also dementia or Alzheimer's disease as the most frequent neurodegenerative disease. Finally, methodological limitations and future perspectives are discussed.
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Affiliation(s)
- Raúl Delgado-Morales
- Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), 3rd Floor, Hospital Duran i Reynals, Av. Gran Via 199-203, 08908L'Hospitalet, Barcelona, Catalonia Spain.,Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands
| | - Roberto Carlos Agís-Balboa
- Psychiatric Diseases Research Group, Galicia Sur Health Research Institute, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, CIBERSAM, Vigo, Spain
| | - Manel Esteller
- Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), 3rd Floor, Hospital Duran i Reynals, Av. Gran Via 199-203, 08908L'Hospitalet, Barcelona, Catalonia Spain.,Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - María Berdasco
- Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), 3rd Floor, Hospital Duran i Reynals, Av. Gran Via 199-203, 08908L'Hospitalet, Barcelona, Catalonia Spain
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29
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Wang SE, Ko SY, Jo S, Choi M, Lee SH, Jo HR, Seo JY, Lee SH, Kim YS, Jung SJ, Son H. TRPV1 Regulates Stress Responses through HDAC2. Cell Rep 2017; 19:401-412. [DOI: 10.1016/j.celrep.2017.03.050] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 02/22/2017] [Accepted: 03/16/2017] [Indexed: 11/25/2022] Open
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30
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Li X, Bao X, Wang R. Neurogenesis-based epigenetic therapeutics for Alzheimer's disease (Review). Mol Med Rep 2016; 14:1043-53. [DOI: 10.3892/mmr.2016.5390] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 04/14/2016] [Indexed: 11/06/2022] Open
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31
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Srebniak MI, van Zutven LJCM, Petit F, Bouquillon S, van Heel IPJ, Knapen MFCM, Cornette JMJ, Kremer A, Van Opstal D, Diderich KEM. Interstitial 6q21q23 duplication - variant of variable phenotype and incomplete penetrance or benign duplication? Mol Cytogenet 2016; 9:43. [PMID: 27274769 PMCID: PMC4891832 DOI: 10.1186/s13039-016-0253-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 05/24/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Chromosome 6q duplication syndrome is a chromosome abnormality associated with characteristic phenotypic features such as intellectual disability (ID), short stature, feeding difficulties, microcephaly, dysmorphic features (prominent forehead, downslanting palpebral fissures, flat nasal bridge, tented upper lip, micrognathia, short webbed neck) and joint contractures. Only a few cases of pure partial 6q trisomy have been published and the severity of the phenotype seems to depend on the breakpoint position. Unfortunately, most of these cases were identified using karyotyping or FISH, so breakpoints at the molecular level and thus gene content are not known. CASES PRESENTATION We report the first two families with an interstitial 6q duplication identified by karyotyping where the gene content and breakpoints were characterized with microarray. In family 1, the 6q22.1q23.2 duplication was detected in a female patient with ID. In family 2, the 6q21q22.33 duplication was identified in a male fetus with multiple congenital malformations. In both families, the duplication seems to show phenotypic heterogeneity and in family 1 also incomplete penetrance suggesting the co-existence of an "additional hit" in affected patients. This "additional hit" was identified in the first family to be a microduplication in 16p11.2, a known susceptibility locus (SL) for neurodevelopmental disorders, that co-segregated with an abnormal phenotype in the affected family members. CONCLUSIONS Our study shows that interstitial 6q21q23 duplication may represent a private variant that is benign, but may also contribute to developmental disorders of variable expressivity in a "multi-hit" model. Finding the "additional hit" within the family is therefore very important for genetic counseling and assessment of the CNV penetrance within the particular family.
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Affiliation(s)
- Malgorzata I Srebniak
- Department of Clinical Genetics, Erasmus MC, Ee2475, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
| | - Laura J C M van Zutven
- Department of Clinical Genetics, Erasmus MC, Ee2475, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
| | - Florence Petit
- Department of Clinical Genetics, University Hospital, Lille, France
| | | | - Ilse P J van Heel
- Department of Clinical Genetics, Erasmus MC, Ee2475, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
| | - Maarten F C M Knapen
- Department of Obstetrics and Gynecology, subdivision Obstetrics and Prenatal Medicine, Erasmus MC, Rotterdam, The Netherlands ; Stichting Prenatale Screening Zuidwest Nederland, Wytemaweg 80, Na-1509, 3015, GE Na-1503 Rotterdam, The Netherlands
| | - Jerome M J Cornette
- Department of Obstetrics and Gynecology, subdivision Obstetrics and Prenatal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Andreas Kremer
- Department of Bioinformatics Erasmus MC, Rotterdam, The Netherlands
| | - Diane Van Opstal
- Department of Clinical Genetics, Erasmus MC, Ee2475, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
| | - Karin E M Diderich
- Department of Clinical Genetics, Erasmus MC, Ee2475, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
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32
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Hsieh J, Zhao X. Genetics and Epigenetics in Adult Neurogenesis. Cold Spring Harb Perspect Biol 2016; 8:cshperspect.a018911. [PMID: 27143699 DOI: 10.1101/cshperspect.a018911] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The cellular basis of adult neurogenesis is neural stem cells residing in restricted areas of the adult brain. These cells self-renew and are multipotent. The maintenance of "stemness" and commitment to differentiation are tightly controlled by intricate molecular networks. Epigenetic mechanisms, including chromatin remodeling, DNA methylation, and noncoding RNAs (ncRNAs), have profound regulatory roles in mammalian gene expression. Significant advances have been made regarding the dynamic roles of epigenetic modulation and function. It has become evident that epigenetic regulators are key players in neural-stem-cell self-renewal, fate specification, and final maturation of new neurons, therefore, adult neurogenesis. Altered epigenetic regulation can result in a number of neurological and neurodevelopmental disorders. Here, we review recent discoveries that advance our knowledge in epigenetic regulation of mammalian neural stem cells and neurogenesis. Insights from studies of epigenetic gene regulation in neurogenesis may lead to new therapies for the treatment of neurodevelopmental disorders.
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Affiliation(s)
- Jenny Hsieh
- Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, Texas 75390
| | - Xinyu Zhao
- Department of Neuroscience and Waisman Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705
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33
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Lim DA, Alvarez-Buylla A. The Adult Ventricular-Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis. Cold Spring Harb Perspect Biol 2016; 8:cshperspect.a018820. [PMID: 27048191 DOI: 10.1101/cshperspect.a018820] [Citation(s) in RCA: 439] [Impact Index Per Article: 48.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A large population of neural stem/precursor cells (NSCs) persists in the ventricular-subventricular zone (V-SVZ) located in the walls of the lateral brain ventricles. V-SVZ NSCs produce large numbers of neuroblasts that migrate a long distance into the olfactory bulb (OB) where they differentiate into local circuit interneurons. Here, we review a broad range of discoveries that have emerged from studies of postnatal V-SVZ neurogenesis: the identification of NSCs as a subpopulation of astroglial cells, the neurogenic lineage, new mechanisms of neuronal migration, and molecular regulators of precursor cell proliferation and migration. It has also become evident that V-SVZ NSCs are regionally heterogeneous, with NSCs located in different regions of the ventricle wall generating distinct OB interneuron subtypes. Insights into the developmental origins and molecular mechanisms that underlie the regional specification of V-SVZ NSCs have also begun to emerge. Other recent studies have revealed new cell-intrinsic molecular mechanisms that enable lifelong neurogenesis in the V-SVZ. Finally, we discuss intriguing differences between the rodent V-SVZ and the corresponding human brain region. The rapidly expanding cellular and molecular knowledge of V-SVZ NSC biology provides key insights into postnatal neural development, the origin of brain tumors, and may inform the development regenerative therapies from cultured and endogenous human neural precursors.
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Affiliation(s)
- Daniel A Lim
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, Department of Neurological Surgery, University of California, San Francisco, California 94143
| | - Arturo Alvarez-Buylla
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, Department of Neurological Surgery, University of California, San Francisco, California 94143
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34
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Epigenetic Mechanisms in Developmental Alcohol-Induced Neurobehavioral Deficits. Brain Sci 2016; 6:brainsci6020012. [PMID: 27070644 PMCID: PMC4931489 DOI: 10.3390/brainsci6020012] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 03/17/2016] [Accepted: 04/05/2016] [Indexed: 12/22/2022] Open
Abstract
Alcohol consumption during pregnancy and its damaging consequences on the developing infant brain are significant public health, social, and economic issues. The major distinctive features of prenatal alcohol exposure in humans are cognitive and behavioral dysfunction due to damage to the central nervous system (CNS), which results in a continuum of disarray that is collectively called fetal alcohol spectrum disorder (FASD). Many rodent models have been developed to understand the mechanisms of and to reproduce the human FASD phenotypes. These animal FASD studies have provided several molecular pathways that are likely responsible for the neurobehavioral abnormalities that are associated with prenatal alcohol exposure of the developing CNS. Recently, many laboratories have identified several immediate, as well as long-lasting, epigenetic modifications of DNA methylation, DNA-associated histone proteins and microRNA (miRNA) biogenesis by using a variety of epigenetic approaches in rodent FASD models. Because DNA methylation patterns, DNA-associated histone protein modifications and miRNA-regulated gene expression are crucial for synaptic plasticity and learning and memory, they can therefore offer an answer to many of the neurobehavioral abnormalities that are found in FASD. In this review, we briefly discuss the current literature of DNA methylation, DNA-associated histone proteins modification and miRNA and review recent developments concerning epigenetic changes in FASD.
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35
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Insights into the Biology and Therapeutic Applications of Neural Stem Cells. Stem Cells Int 2016; 2016:9745315. [PMID: 27069486 PMCID: PMC4812498 DOI: 10.1155/2016/9745315] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 02/08/2016] [Indexed: 12/27/2022] Open
Abstract
The cerebral cortex is essential for our higher cognitive functions and emotional reasoning. Arguably, this brain structure is the distinguishing feature of our species, and yet our remarkable cognitive capacity has seemingly come at a cost to the regenerative capacity of the human brain. Indeed, the capacity for regeneration and neurogenesis of the brains of vertebrates has declined over the course of evolution, from fish to rodents to primates. Nevertheless, recent evidence supporting the existence of neural stem cells (NSCs) in the adult human brain raises new questions about the biological significance of adult neurogenesis in relation to ageing and the possibility that such endogenous sources of NSCs might provide therapeutic options for the treatment of brain injury and disease. Here, we highlight recent insights and perspectives on NSCs within both the developing and adult cerebral cortex. Our review of NSCs during development focuses upon the diversity and therapeutic potential of these cells for use in cellular transplantation and in the modeling of neurodevelopmental disorders. Finally, we describe the cellular and molecular characteristics of NSCs within the adult brain and strategies to harness the therapeutic potential of these cell populations in the treatment of brain injury and disease.
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36
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Sousa N. The dynamics of the stress neuromatrix. Mol Psychiatry 2016; 21:302-12. [PMID: 26754952 PMCID: PMC4759204 DOI: 10.1038/mp.2015.196] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Revised: 10/04/2015] [Accepted: 10/21/2015] [Indexed: 01/08/2023]
Abstract
Stressful stimuli in healthy subjects trigger activation of a consistent and reproducible set of brain regions; yet, the notion that there is a single and constant stress neuromatrix is not sustainable. Indeed, after chronic stress exposure there is activation of many brain regions outside that network. This suggests that there is a distinction between the acute and the chronic stress neuromatrix. Herein, a new working model is proposed to understand the shift between these networks. The understanding of the factors that modulate these networks and their interplay will allow for a more comprehensive and holistic perspective of how the brain shifts 'back and forth' from a healthy to a stressed pattern and, ultimately, how the latter can be a trigger for several neurological and psychiatric conditions.
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Affiliation(s)
- N Sousa
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, Braga, Portugal,ICVS/3B's–PT Government Associate Laboratory, Braga/Guimarães, Portugal,Clinical Academic Center–Braga, Braga, Portugal,Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, Braga 4710-057, Portugal. E-mail:
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37
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38
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Role of Epigenetics in Stem Cell Proliferation and Differentiation: Implications for Treating Neurodegenerative Diseases. Int J Mol Sci 2016; 17:ijms17020199. [PMID: 26848657 PMCID: PMC4783933 DOI: 10.3390/ijms17020199] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Revised: 01/17/2016] [Accepted: 01/27/2016] [Indexed: 12/15/2022] Open
Abstract
The main objectives of this review are to survey the current literature on the role of epigenetics in determining the fate of stem cells and to assess how this information can be used to enhance the treatment strategies for some neurodegenerative disorders, like Huntington’s disease, Parkinson’s disease and Alzheimer’s disease. Some of these epigenetic mechanisms include DNA methylation and histone modifications, which have a direct impact on the way that genes are expressed in stem cells and how they drive these cells into a mature lineage. Understanding how the stem cells are behaving and giving rise to mature cells can be used to inform researchers on effective ways to design stem cell-based treatments. In this review article, the way in which the basic understanding of how manipulating this process can be utilized to treat certain neurological diseases will be presented. Different genetic factors and their epigenetic changes during reprogramming of stem cells into induced pluripotent stem cells (iPSCs) have significant potential for enhancing the efficacy of cell replacement therapies.
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39
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Yao ZH, Kang X, Yang L, Niu Y, Lu Y, Nie L. PBA regulates neurogenesis and cognition dysfunction after repeated electroconvulsive shock in a rat model. Psychiatry Res 2015; 230:331-40. [PMID: 26381183 DOI: 10.1016/j.psychres.2015.09.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 09/01/2015] [Accepted: 09/07/2015] [Indexed: 12/23/2022]
Abstract
Electroconvulsive therapy (ECT) was widely used to treat the refractory depression. But ECT led to the cognitive deficits plaguing the depression patients. The underlying mechanisms of the cognitive deficits remain elusive. Repeated electroconvulsive shock (rECS) was used to simulate ECT and explore the mechanisms of ECT during the animal studies. Previous studies showed rECS could lead to neurogenesis and cognitive impairment. But it was well known that neurogenesis could improve the cognition. So these suggested that the mechanism of the cognitive deficit after rECS was very complex. In present study, we explored the probable mechanisms of the cognitive deficit after rECS from neurogenesis aspect. We found the cognitive deficit was reversible and neurogenesis could bring a long-term beneficial effect on cognition. Astrogliosis and NR1 down-regulation probably participated in the reversible cognitive deficits after rECS. Phenylbutyric acid (PBA), generally as an agent to investigate the roles of histone acetylation, could prevent the reversible cognitive dysfunction, but PBA could diminish the long-term effect of enhanced cognition by rECS. These suggested that ECT could possibly bring the long-term beneficial cognitive effect by regulating neurogenesis.
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Affiliation(s)
- Zhao-Hui Yao
- Department of Geriatrics, Renmin Hospital of Wuhan University, #238 Jiefang Road, Wuhan 430060, China; Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xiang Kang
- Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liu Yang
- Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Niu
- Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ye Lu
- Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Nie
- Department of Geriatrics, Renmin Hospital of Wuhan University, #238 Jiefang Road, Wuhan 430060, China
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Neuronal gene repression in Niemann-Pick type C models is mediated by the c-Abl/HDAC2 signaling pathway. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2015; 1859:269-79. [PMID: 26603102 DOI: 10.1016/j.bbagrm.2015.11.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 11/05/2015] [Accepted: 11/17/2015] [Indexed: 12/26/2022]
Abstract
BACKGROUND Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. There are currently no effective FDA-approved treatments for NPC, although in the last years the inhibition of histone deacetylases (HDACs) has emerged as a potential treatment for this disease. However, the molecular mechanisms that deregulate HDAC activity in NPC disease are unknown. Previously our group had shown that the proapoptotic tyrosine kinase c-Abl signaling is activated in NPC neurons. Here, we demonstrate that c-Abl activity increases HDAC2 levels inducing neuronal gene repression of key synaptic genes in NPC models. RESULTS Our data show that: i) HDAC2 levels and activity are increased in NPC neuronal models and in Npc1(-/-) mice; ii) inhibition of c-Abl or c-Abl deficiency prevents the increase of HDAC2 protein levels and activity in NPC neuronal models; iii) c-Abl inhibition decreases the levels of HDAC2 tyrosine phosphorylation; iv) treatment with methyl-β-cyclodextrin and vitamin E decreases the activation of the c-Abl/HDAC2 pathway in NPC neurons; v) in vivo treatment with two c-Abl inhibitors prevents the increase of HDAC2 protein levels in the brain of Npc1(-/-) mice; and vi) c-Abl inhibition prevents HDAC2 recruitment to the promoter of neuronal genes, triggering an increase in their expression. CONCLUSION Our data show the involvement of the c-Abl/HDAC2 signaling pathway in the regulation of neuronal gene expression in NPC neuronal models. Thus, inhibition of c-Abl could be a pharmacological target for preventing the deleterious effects of increased HDAC2 levels in NPC disease.
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Stengel KR, Hiebert SW. Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy. Antioxid Redox Signal 2015; 23:51-65. [PMID: 24730655 PMCID: PMC4492608 DOI: 10.1089/ars.2014.5915] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
SIGNIFICANCE The contribution of epigenetic alterations to cancer development and progression is becoming increasingly clear, prompting the development of epigenetic therapies. Histone deacetylase inhibitors (HDIs) represent one of the first classes of such therapy. Two HDIs, Vorinostat and Romidepsin, are broad-spectrum inhibitors that target multiple histone deacetylases (HDACs) and are FDA approved for the treatment of cutaneous T-cell lymphoma. However, the mechanism of action and the basis for the cancer-selective effects of these inhibitors are still unclear. RECENT ADVANCES While the anti-tumor effects of HDIs have traditionally been attributed to their ability to modify gene expression after the accumulation of histone acetylation, recent studies have identified the effects of HDACs on DNA replication, DNA repair, and genome stability. In addition, the HDIs available in the clinic target multiple HDACs, making it difficult to assign either their anti-tumor effects or their associated toxicities to the inhibition of a single protein. However, recent studies in mouse models provide insights into the tissue-specific functions of individual HDACs and their involvement in mediating the effects of HDI therapy. CRITICAL ISSUES Here, we describe how altered replication contributes to the efficacy of HDAC-targeted therapies as well as discuss what knowledge mouse models have provided to our understanding of the specific functions of class I HDACs, their potential involvement in tumorigenesis, and how their disruption may contribute to toxicities associated with HDI treatment. FUTURE DIRECTIONS Impairment of DNA replication by HDIs has important therapeutic implications. Future studies should assess how best to exploit these findings for therapeutic gain.
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Affiliation(s)
- Kristy R. Stengel
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Scott W. Hiebert
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
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Montalbán-Loro R, Domingo-Muelas A, Bizy A, Ferrón SR. Epigenetic regulation of stemness maintenance in the neurogenic niches. World J Stem Cells 2015; 7:700-710. [PMID: 26029342 PMCID: PMC4444611 DOI: 10.4252/wjsc.v7.i4.700] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 12/12/2014] [Accepted: 03/20/2015] [Indexed: 02/06/2023] Open
Abstract
In the adult mouse brain, the subventricular zone lining the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus are two zones that contain neural stem cells (NSCs) with the capacity to give rise to neurons and glia during the entire life of the animal. Spatial and temporal regulation of gene expression in the NSCs population is established and maintained by the coordinated interaction between transcription factors and epigenetic regulators which control stem cell fate. Epigenetic mechanisms are heritable alterations in genome function that do not involve changes in DNA sequence itself but that modulate gene expression, acting as mediators between the environment and the genome. At the molecular level, those epigenetic mechanisms comprise chemical modifications of DNA such as methylation, hydroxymethylation and histone modifications needed for the maintenance of NSC identity. Genomic imprinting is another normal epigenetic process leading to parental-specific expression of a gene, known to be implicated in the control of gene dosage in the neurogenic niches. The generation of induced pluripotent stem cells from NSCs by expression of defined transcription factors, provide key insights into fundamental principles of stem cell biology. Epigenetic modifications can also occur during reprogramming of NSCs to pluripotency and a better understanding of this process will help to elucidate the mechanisms required for stem cell maintenance. This review takes advantage of recent studies from the epigenetic field to report knowledge regarding the mechanisms of stemness maintenance of neural stem cells in the neurogenic niches.
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Tassano E, Mirabelli-Badenier M, Veneselli E, Puliti A, Lerone M, Vaccari CM, Morana G, Porta S, Gimelli G, Cuoco C. Clinical and molecular characterization of a patient with interstitial 6q21q22.1 deletion. Mol Cytogenet 2015; 8:31. [PMID: 26052347 PMCID: PMC4457201 DOI: 10.1186/s13039-015-0134-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 02/27/2015] [Indexed: 11/13/2022] Open
Abstract
Background Interstitial 6q deletions, involving the 6q15q25 chromosomal region, are rare events characterized by variable phenotypes and no clear karyotype/phenotype correlation has been determined yet. Results We present a child with a 6q21q22.1 deletion, characterized by array-CGH, associated with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, skeletal, muscle, and brain anomalies. Discussion In our patient, the 6q21q22.1 deleted region contains ten genes (TRAF3IP2, FYN, WISP3, TUBE1, LAMA4, MARCKS, HDAC2, HS3ST5, FRK, COL10A1) and two desert gene regions. We discuss here if these genes had some role in determining the phenotype of our patient in order to establish a possible karyotype/phenotype correlation. Electronic supplementary material The online version of this article (doi:10.1186/s13039-015-0134-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Elisa Tassano
- Laboratorio di Citogenetica, Istituto Giannina Gaslini, L.goG.Gaslini 5, 16147 Genova, Italy
| | - Marisol Mirabelli-Badenier
- Child Neuropsychiatry Unit, Department of Neurosciences and Rehabilitation, Istituto Giannina Gaslini, Genoa, Italy
| | - Edvige Veneselli
- Child Neuropsychiatry Unit, Department of Neurosciences and Rehabilitation, Istituto Giannina Gaslini, Genoa, Italy
| | - Aldamaria Puliti
- Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy ; U.O.C. Genetica Medica, Istituto Giannina Gaslini, Genova, Italy
| | | | - Carlotta Maria Vaccari
- Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
| | - Giovanni Morana
- Pediatric Neuroradiology Unit, Istituto Giannina Gaslini, Genoa, Italy
| | - Simona Porta
- Laboratorio di Citogenetica, Istituto Giannina Gaslini, L.goG.Gaslini 5, 16147 Genova, Italy
| | - Giorgio Gimelli
- Laboratorio di Citogenetica, Istituto Giannina Gaslini, L.goG.Gaslini 5, 16147 Genova, Italy
| | - Cristina Cuoco
- Laboratorio di Citogenetica, Istituto Giannina Gaslini, L.goG.Gaslini 5, 16147 Genova, Italy
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O'Leary CJ, Bradford D, Chen M, White A, Blackmore DG, Cooper HM. The Netrin/RGM Receptor, Neogenin, Controls Adult Neurogenesis by Promoting Neuroblast Migration and Cell Cycle Exit. Stem Cells 2015; 33:503-14. [DOI: 10.1002/stem.1861] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 07/31/2014] [Accepted: 09/06/2014] [Indexed: 01/16/2023]
Affiliation(s)
- Conor J. O'Leary
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
| | - DanaKai Bradford
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
| | - Min Chen
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
| | - Amanda White
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
| | - Daniel G. Blackmore
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
| | - Helen M. Cooper
- The University of Queensland, Queensland Brain Institute; Brisbane Queensland Australia
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Swaminathan A, Kumar M, Halder Sinha S, Schneider-Anthony A, Boutillier AL, Kundu TK. Modulation of neurogenesis by targeting epigenetic enzymes using small molecules: an overview. ACS Chem Neurosci 2014; 5:1164-77. [PMID: 25250644 DOI: 10.1021/cn500117a] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Neurogenesis consists of a plethora of complex cellular processes including neural stem cell (NSC) proliferation, migration, maturation or differentiation to neurons, and finally integration into the pre-existing neural circuits in the brain, which are temporally regulated and coordinated sequentially. Mammalian neurogenesis begins during embryonic development and continues in postnatal brain (adult neurogenesis). It is now evident that adult neurogenesis is driven by extracellular and intracellular signaling pathways, where epigenetic modifications like reversible histone acetylation, methylation, as well as DNA methylation play a vital role. Epigenetic regulation of gene expression during neural development is governed mainly by histone acetyltransferases (HATs), histone methyltransferase (HMTs), DNA methyltransferases (DNMTs), and also the enzymes for reversal, like histone deacetylases (HDACs), and many of these have also been shown to be involved in the regulation of adult neurogenesis. The contribution of these epigenetic marks to neurogenesis is increasingly being recognized, through knockout studies and small molecule modulator based studies. These small molecules are directly involved in regeneration and repair of neurons, and not only have applications from a therapeutic point of view, but also provide a tool to study the process of neurogenesis itself. In the present Review, we will focus on small molecules that act predominantly on epigenetic enzymes to enhance neurogenesis and neuroprotection and discuss the mechanism and recent advancements in their synthesis, targeting, and biology.
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Affiliation(s)
- Amrutha Swaminathan
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
| | - Manoj Kumar
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
| | - Sarmistha Halder Sinha
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
| | - Anne Schneider-Anthony
- Laboratoire de Neurosciences
Cognitives et Adaptatives (LNCA), UMR7364, Université de Strasbourg-CNRS,
GDR CNRS 2905, Faculté de Psychologie, 12 rue Goethe, 67000 Strasbourg, France
| | - Anne-Laurence Boutillier
- Laboratoire de Neurosciences
Cognitives et Adaptatives (LNCA), UMR7364, Université de Strasbourg-CNRS,
GDR CNRS 2905, Faculté de Psychologie, 12 rue Goethe, 67000 Strasbourg, France
| | - Tapas K Kundu
- Transcription and
Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O, Bangalore-560064, India
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Lim DA, Alvarez-Buylla A. Adult neural stem cells stake their ground. Trends Neurosci 2014; 37:563-71. [PMID: 25223700 DOI: 10.1016/j.tins.2014.08.006] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 08/19/2014] [Accepted: 08/21/2014] [Indexed: 02/07/2023]
Abstract
The birth of new neurons in the walls of the adult brain lateral ventricles has captured the attention of many neuroscientists for over 2 decades, yielding key insights into the identity and regulation of neural stem cells (NSCs). In the adult ventricular-subventricular zone (V-SVZ), NSCs are a specialized form of astrocyte that generates several types of neurons for the olfactory bulb. In this review, we discuss recent findings regarding the unique organization of the V-SVZ NSC niche, the multiple regulatory controls of neuronal production, the distinct regional identities of adult NSCs, and the epigenetic mechanisms that maintain adult neurogenesis. Understanding how V-SVZ NSCs establish and maintain lifelong neurogenesis continues to provide surprising insights into the cellular and molecular regulation of neural development.
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Affiliation(s)
- Daniel A Lim
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, CA 94143, USA.
| | - Arturo Alvarez-Buylla
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
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Gonzalez-Zuñiga M, Contreras PS, Estrada LD, Chamorro D, Villagra A, Zanlungo S, Seto E, Alvarez AR. c-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease. Mol Cell 2014; 56:163-73. [PMID: 25219501 DOI: 10.1016/j.molcel.2014.08.013] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 07/02/2014] [Accepted: 08/07/2014] [Indexed: 10/24/2022]
Abstract
In Alzheimer's disease (AD), there is a decrease in neuronal gene expression induced by HDAC2 increase; however, the mechanisms involved are not fully elucidated. Here, we described how the tyrosine kinase c-Abl increases HDAC2 levels, inducing transcriptional repression of synaptic genes. Our data demonstrate that (1) in neurons, c-Abl inhibition with Imatinib prevents the AβO-induced increase in HDAC2 levels; (2) c-Abl knockdown cells show a decrease in HDAC2 levels, while c-Abl overexpression increases them; (3) c-Abl inhibition reduces HDAC2-dependent repression activity and HDAC2 recruitment to the promoter of several synaptic genes, increasing their expression; (4) c-Abl induces tyrosine phosphorylation of HDAC2, a posttranslational modification, affecting both its stability and repression activity; and (5) treatment with Imatinib decreases HDAC2 levels in a transgenic mice model of AD. Our results support the participation of the c-Abl/HDAC2 signaling pathway in the epigenetic blockade of gene expression in AD pathology.
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Affiliation(s)
- Marcelo Gonzalez-Zuñiga
- Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile; Biological and Chemistry Sciences Department, Universidad Bernardo O'Higgins, Santiago 8370993, Chile
| | - Pablo S Contreras
- Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile; Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile
| | - Lisbell D Estrada
- Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile; Biological and Chemistry Sciences Department, Universidad Bernardo O'Higgins, Santiago 8370993, Chile
| | - David Chamorro
- Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile
| | - Alejandro Villagra
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Silvana Zanlungo
- Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile
| | - Edward Seto
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Alejandra R Alvarez
- Department of Cell & Molecular Biology, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.
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Santos AI, Martínez-Ruiz A, Araújo IM. S-nitrosation and neuronal plasticity. Br J Pharmacol 2014; 172:1468-78. [PMID: 24962517 DOI: 10.1111/bph.12827] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Revised: 05/08/2014] [Accepted: 06/09/2014] [Indexed: 12/22/2022] Open
Abstract
Nitric oxide (NO) has long been recognized as a multifaceted participant in brain physiology. Despite the knowledge that was gathered over many years regarding the contribution of NO to neuronal plasticity, for example the ability of the brain to change in response to new stimuli, only in recent years have we begun to understand how NO acts on the molecular and cellular level to orchestrate such important phenomena as synaptic plasticity (modification of the strength of existing synapses) or the formation of new synapses (synaptogenesis) and new neurons (neurogenesis). Post-translational modification of proteins by NO derivatives or reactive nitrogen species is a non-classical mechanism for signalling by NO. S-nitrosation is a reversible post-translational modification of thiol groups (mainly on cysteines) that may result in a change of function of the modified protein. S-nitrosation of key target proteins has emerged as a main regulatory mechanism by which NO can influence several levels of brain plasticity, which are reviewed in this work. Understanding how S-nitrosation contributes to neural plasticity can help us to better understand the physiology of these processes, and to better address pathological changes in plasticity that are involved in the pathophysiology of several neurological diseases.
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Affiliation(s)
- A I Santos
- Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal; IBB - Institute for Biotechnology and Bioengineering, Centre for Molecular and Structural Biomedicine, University of Algarve, Faro, Portugal; Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
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HDAC3 controls gap 2/mitosis progression in adult neural stem/progenitor cells by regulating CDK1 levels. Proc Natl Acad Sci U S A 2014; 111:13541-6. [PMID: 25161285 DOI: 10.1073/pnas.1411939111] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The maintenance of the resident adult neural stem/progenitor cell (NSPC) pool depends on the precise balance of proliferation, differentiation, and maintenance of the undifferentiated state. Identifying the mechanisms that regulate this balance in adult hippocampal NSPCs can provide insight into basic stem cell self-renewal principles important for tissue homeostasis and preventing tumor formation. Pharmacological inhibition of histone deacetylases (HDACs), a class of histone-modifying enzymes, have promising effects in cancer cells, yet the specific roles of individual HDACs in stem cell proliferation is unclear. Here using conditional KO (cKO) mice and in vitro cell culture, we show that histone deacetylase 3 (HDAC3) is required for the proliferation of adult NSPCs. Detailed cell cycle analysis of NSPCs from Hdac3 cKO mice reveals a defect in cell cycle progression through the gap 2/mitosis (G2/M) but not the S phase. Moreover, HDAC3 controls G2/M phase progression mainly through posttranslational stabilization of the G2/M cyclin-dependent kinase 1 (CDK1). These results demonstrate that HDAC3 plays a critical role in NSPC proliferation and suggest that strategies aimed at pharmacological modulation of HDAC3 may be beneficial for tissue regeneration and controlling tumor cell growth.
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The link between injury-induced stress and regenerative phenomena: A cellular and genetic synopsis. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2014; 1849:454-61. [PMID: 25088176 DOI: 10.1016/j.bbagrm.2014.07.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 07/25/2014] [Accepted: 07/28/2014] [Indexed: 12/24/2022]
Abstract
Injury is an inescapable phenomenon of life that affects animals at every physiological level. Yet, some animals respond to injury by rebuilding the damaged tissues whereas others are limited to scarring. Elucidating how a tissue insult from wounding leads to a regenerative response at the genetic level is essential to make regenerative advantages translational. It has become clear that animals with regenerative abilities recycle developmental programs after injury, reactivating genes that have lied dormant throughout adulthood. The question that is critical to our understanding of regeneration is how a specific set of developmentally important genes can be reactivated only after an acute tissue insult. Here, we review how injury-induced cellular stresses such as hypoxic, oxidative, and mechanical stress may contribute to the genomic and epigenetic changes that promote regeneration in animals. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity.
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