The Histone Demethylases Jhdm1a/1b Enhance Somatic Cell Reprogramming in a Vitamin-C-Dependent Manner

• Published in: Cell stem cell Vol. 9; no. 6; pp. 575 - 587
• Main Authors: Wang, Tao, Chen, Keshi, Zeng, Xiaoming, Yang, Jianguo, Wu, Yun, Shi, Xi, Qin, Baoming, Zeng, Lingwen, Esteban, Miguel Angel, Pan, Guangjin, Pei, Duanqing
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 02-12-2011; Cell Press
• Subjects: Animals; Antioxidants - pharmacology; Ascorbic Acid - pharmacology; Biological and medical sciences; Cell Cycle - physiology; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cells, Cultured; Cellular Reprogramming - drug effects; Cellular Senescence - physiology; F-Box Proteins - genetics; F-Box Proteins - metabolism; Fibroblasts - cytology; Fibroblasts - physiology; Fundamental and applied biological sciences. Psychology; Histones - genetics; Histones - metabolism; Humans; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Lysine - metabolism; Mice; Mice, Transgenic; Molecular and cellular biology; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - physiology; Cellular reprogramming; Somatic cell; Histone; Vitamin; Retinol
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2011.10.005

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.
[Display omitted]
► Vitamin C reduces H3K36me2/3 levels through the demethylases
Jhdm1a/1b ►
Jhdm1a/1b enhance somatic cell reprogramming ►
Jhdm1b and vitamin C suppress senescence and enhance cell proliferation ►
Jhdm1b cooperates with
Oct4 to activate the microRNA 302/367 cluster