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

Cell Stem Cell. 2011 Dec 2;9(6):575-87. doi: 10.1016/j.stem.2011.10.005. Epub 2011 Nov 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Ascorbic Acid / pharmacology*
  • Cell Cycle / physiology
  • Cells, Cultured
  • Cellular Reprogramming / drug effects*
  • Cellular Senescence / physiology
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Lysine / metabolism
  • Mice
  • Mice, Transgenic
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / physiology*

Substances

  • Antioxidants
  • F-Box Proteins
  • Histones
  • Octamer Transcription Factor-3
  • FBXL11 protein, mouse
  • Jumonji Domain-Containing Histone Demethylases
  • Kdm2b protein, mouse
  • Lysine
  • Ascorbic Acid

Associated data

  • GEO/GSE32994