title: H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs.
abstract: The induction of pluripotent stem cells (iPSCs) by defined factors is poorly understood stepwise. Here, we show that histone H3 lysine 9 (H3K9) methylation is the primary epigenetic determinant for the intermediate pre-iPSC state, and its removal leads to fully reprogrammed iPSCs. We generated a panel of stable pre-iPSCs that exhibit pluripotent properties but do not activate the core pluripotency network, although they remain sensitive to vitamin C for conversion into iPSCs. Bone morphogenetic proteins (BMPs) were subsequently identified in serum as critical signaling molecules in arresting reprogramming at the pre-iPSC state. Mechanistically, we identified H3K9 methyltransferases as downstream targets of BMPs and showed that they function with their corresponding demethylases as the on/off switch for the pre-iPSC fate by regulating H3K9 methylation status at the core pluripotency loci. Our results not only establish pre-iPSCs as an epigenetically stable signpost along the reprogramming road map, but they also provide mechanistic insights into the epigenetic reprogramming of cell fate.
authors.affiliation: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Jiekai
authors.initials: J
authors.lastname: Chen
authors.forename: He
authors.initials: H
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Qi
authors.forename: Bei
authors.initials: B
authors.lastname: Wei
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Yang
authors.forename: Hanquan
authors.initials: H
authors.lastname: Liang
authors.forename: You
authors.initials: Y
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Yaran
authors.initials: Y
authors.lastname: Wu
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.forename: Jieying
authors.initials: J
authors.lastname: Zhu
authors.forename: Xiangjie
authors.initials: X
authors.lastname: Zhao
authors.forename: Tianran
authors.initials: T
authors.lastname: Peng
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shen
authors.initials: S
authors.lastname: Chen
authors.forename: Xuejia
authors.initials: X
authors.lastname: Li
authors.forename: Dongwei
authors.initials: D
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Duanqing
authors.initials: D
authors.lastname: Pei
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000097:blood / Q000378:metabolism; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002460:Cell Line; D065150:Cellular Reprogramming / Q000235:genetics; D016000:Cluster Analysis; D053595:Embryonic Stem Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; D006657:Histones; D008780:Methyltransferases