title: PHB Associates with the HIRA Complex to Control an Epigenetic-Metabolic Circuit in Human ESCs.
abstract: The chromatin landscape and cellular metabolism both contribute to cell fate determination, but their interplay remains poorly understood. Using genome-wide siRNA screening, we have identified prohibitin (PHB) as an essential factor in self-renewal of human embryonic stem cells (hESCs). Mechanistically, PHB forms protein complexes with HIRA, a histone H3.3 chaperone, and stabilizes the protein levels of HIRA complex components. Like PHB, HIRA is required for hESC self-renewal. PHB and HIRA act together to control global deposition of histone H3.3 and gene expression in hESCs. Of particular note, PHB and HIRA regulate the chromatin architecture at the promoters of isocitrate dehydrogenase genes to promote transcription and, thus, production of α-ketoglutarate, a key metabolite in the regulation of ESC fate. Our study shows that PHB has an unexpected nuclear role in hESCs that is required for self-renewal and that it acts with HIRA in chromatin organization to link epigenetic organization to a metabolic circuit.
authors.affiliation: Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, 320 Yueyang Road, Shanghai 200032, China; University of Chinese Academy of Sciences, 19A Yuquan Rd, Shijingshan Distinct 100049, PRC.
authors.forename: Zhexin
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, 320 Yueyang Road, Shanghai 200032, China.
authors.forename: Chunliang
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Molecular Developmental Biology, Institute of Medical Sciences, Shanghai JiaoTong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: Yanwu
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, 320 Yueyang Road, Shanghai 200032, China; University of Chinese Academy of Sciences, 19A Yuquan Rd, Shijingshan Distinct 100049, PRC.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Molecular Developmental Biology, Institute of Medical Sciences, Shanghai JiaoTong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: Zepeng
authors.initials: Z
authors.lastname: Qu
authors.affiliation: Department of Molecular Developmental Biology, Institute of Medical Sciences, Shanghai JiaoTong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Molecular Developmental Biology, Institute of Medical Sciences, Shanghai JiaoTong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: Laixiang
authors.initials: L
authors.lastname: Ge
authors.affiliation: Department of Molecular Developmental Biology, Institute of Medical Sciences, Shanghai JiaoTong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Tang
authors.affiliation: Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, 320 Yueyang Road, Shanghai 200032, China; University of Chinese Academy of Sciences, 19A Yuquan Rd, Shijingshan Distinct 100049, PRC.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, 320 Yueyang Road, Shanghai 200032, China.
authors.forename: Chenlin
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, 320 Yueyang Road, Shanghai 200032, China; Department of Molecular Developmental Biology, Institute of Medical Sciences, Shanghai JiaoTong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China. Electronic address: yjin@sibs.ac.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D000066673:Cell Self Renewal / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D050437:Genes, Developmental; D015894:Genome, Human; D057809:HEK293 Cells; D056488:Histone Chaperones / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008297:Male; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D000091402:Prohibitins; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; C086057:HIRA protein, human; D056488:Histone Chaperones; D006657:Histones; D007656:Ketoglutaric Acids; C000717328:PHB protein, human; D000091402:Prohibitins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014157:Transcription Factors; D007521:Isocitrate Dehydrogenase
keywords: H3.3; HIRA complexes; PHB; epigenetics; human ESCs; metabolism; self-renewal; α-ketoglutarate