title: Dual roles of histone H3 lysine 9 acetylation in human embryonic stem cell pluripotency and neural differentiation.
abstract: Early neurodevelopment requires cell fate commitment from pluripotent stem cells to restricted neural lineages, which involves the epigenetic regulation of chromatin structure and lineage-specific gene transcription. However, it remains unclear how histone H3 lysine 9 acetylation (H3K9Ac), an epigenetic mark representing transcriptionally active chromatin, is involved in the neural commitment from pluripotent embryonic stem cells (ESCs). In this study, we demonstrate that H3K9Ac gradually declines during the first 4 days of in vitro neural differentiation of human ESCs (hESCs) and then increases during days 4-8. Consistent with this finding, the H3K9Ac enrichment at several pluripotency genes was decreased, and H3K9Ac occupancies at the loci of neurodevelopmental genes increased during hESC neural commitment. Inhibiting H3K9 deacetylation on days 0-4 by histone deacetylase inhibitors (HDACis) promoted hESC pluripotency and suppressed its neural differentiation. Conversely, HDACi-elicited up-regulation of H3K9 acetylation on days 4-8 enhanced neural differentiation and activated multiple neurodevelopmental genes. Mechanistically, HDACis promote pluripotency gene transcription to support hESC self-renewal through suppressing HDAC3 activity. During hESC neural commitment, HDACis relieve the inhibitory activities of HDAC1/5/8 and thereby promote early neurodevelopmental gene expression by interfering with gene-specific histone acetylation patterns. Furthermore, p300 is primarily identified as the major histone acetyltransferase involved in both hESC pluripotency and neural differentiation. Our results indicate that epigenetic modification plays pivotal roles during the early neural specification of hESCs. The histone acetylation, which is regulated by distinct HDAC members at different neurodevelopmental stages, plays dual roles in hESC pluripotency maintenance and neural differentiation.
authors.affiliation: From the State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: From the State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China, the School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China, and.
authors.forename: Xianfa
authors.initials: X
authors.lastname: Yang
authors.affiliation: the Institute of Life Science, Nanchang University, Nanchang, Jiangxi 330031, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Tang
authors.affiliation: From the State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China, njing@sibcb.ac.cn.
authors.forename: Naihe
authors.initials: N
authors.lastname: Jing
mesh_terms: D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000166:cytology*; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry; D006657:Histones / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D008239:Lysine / Q000737:chemistry*; D051379:Mice; D009474:Neurons / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology*; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D050880:p300-CBP Transcription Factors; D008239:Lysine
keywords: Embryonic Stem Cell; Histone Deacetylase Inhibitor (HDAC Inhibitor) (HDI); Histone Modification; Neurodevelopment; Pluripotency