title: Suppression of histone deacetylation promotes the differentiation of human pluripotent stem cells towards neural progenitor cells.
abstract: BACKGROUND
  Emerging studies of human pluripotent stem cells (hPSCs) raise new prospects for neurodegenerative disease modeling and cell replacement therapies. Therefore, understanding the mechanisms underlying the commitment of neural progenitor cells (NPCs) is important for the application of hPSCs in neurodegenerative disease therapies. It has been reported that epigenetic modifications of histones play important roles in neural differentiation, but the exact mechanisms in regulating hPSC differentiation towards NPCs are not fully elucidated.
  
  
  RESULTS
  We demonstrated that suppression of histone deacetylases (HDACs) promoted the differentiation of hPSCs towards NPCs. Application of HDAC inhibitors (HDACi) increased the expression of neuroectodermal markers and enhanced the neuroectodermal specification once neural differentiation was initiated, thereby leading to more NPC generation. Similarly, the transcriptome analysis showed that HDACi increased the expression levels of ectodermal markers and triggered the NPC differentiation related pathways, while decreasing the expression levels of endodermal and mesodermal markers. Furthermore, we documented that HDAC3 but not HDAC1 or HDAC2 was the critical regulator participating in NPC differentiation, and knockdown of HDAC3's cofactor SMRT exhibited a similar effect as HDAC3 on NPC generation.
  
  
  CONCLUSIONS
  Our study reveals that HDACs, especially HDAC3, negatively regulate the differentiation of hPSCs towards NPCs at an earlier stage of neural differentiation. Moreover, HDAC3 might function by forming a repressor complex with its cofactor SMRT during this process. Thus, our findings uncover an important epigenetic mechanism of HDAC3 in the differentiation of hPSCs towards NPCs.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China. yangjuan@sibs.ac.cn.
authors.forename: Juan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China. tangyu-sky@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Center for Translational Research of Neurology Disease, The 1st Affiliated Hospital, Dalian Medical University, Dalian, China. liu_hui0505@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China. fguo@sibs.ac.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China. nijun@sibs.ac.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Ni
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China. wdle@sibs.ac.cn.|Center for Translational Research of Neurology Disease, The 1st Affiliated Hospital, Dalian Medical University, Dalian, China. wdle@sibs.ac.cn.
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D003001:Cloning, Molecular; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D058953:Neural Stem Cells / Q000166:cytology*; D039904:Pluripotent Stem Cells / Q000166:cytology*; D000099186:Histone Deacetylase 3
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D000099186:Histone Deacetylase 3