title: The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner.
abstract: Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) resets the epigenome to an embryonic-like state. Vitamin C enhances the reprogramming process, but the underlying mechanisms are unclear. Here we show that the histone demethylases Jhdm1a/1b are key effectors of somatic cell reprogramming downstream of vitamin C. We first observed that vitamin C induces H3K36me2/3 demethylation in mouse embryonic fibroblasts in culture and during reprogramming. We then identified Jhdm1a/1b, two known vitamin-C-dependent H3K36 demethylases, as potent regulators of reprogramming through gain- and loss-of-function approaches. Furthermore, we found that Jhdm1b accelerates cell cycle progression and suppresses cell senescence during reprogramming by repressing the Ink4/Arf locus. Jhdm1b also cooperates with Oct4 to activate the microRNA cluster 302/367, an integral component of the pluripotency machinery. Our results therefore reveal a role for H3K36me2/3 in cell fate determination and establish a link between histone demethylases and vitamin-C-induced reprogramming.
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 510530, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Keshi
authors.initials: K
authors.lastname: Chen
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zeng
authors.forename: Jianguo
authors.initials: J
authors.lastname: Yang
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.forename: Xi
authors.initials: X
authors.lastname: Shi
authors.forename: Baoming
authors.initials: B
authors.lastname: Qin
authors.forename: Lingwen
authors.initials: L
authors.lastname: Zeng
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Esteban
authors.forename: Guangjin
authors.initials: G
authors.lastname: Pan
authors.forename: Duanqing
authors.initials: D
authors.lastname: Pei
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000187:drug effects*; D016922:Cellular Senescence / Q000502:physiology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology*
chemical_list: D000975:Antioxidants; D044783:F-Box Proteins; D006657:Histones; D050814:Octamer Transcription Factor-3; C547579:FBXL11 protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; C524747:Kdm2b protein, mouse; D008239:Lysine; D001205:Ascorbic Acid