H3K9 Methylation Is a Barrier During Somatic Cell Reprogramming Into iPSCs

Nat Genet. 2013 Jan;45(1):34-42. doi: 10.1038/ng.2491. Epub 2012 Dec 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / blood
  • Bone Morphogenetic Proteins / metabolism
  • Cell Culture Techniques
  • Cell Differentiation
  • Cell Line
  • Cellular Reprogramming* / genetics
  • Cluster Analysis
  • Embryonic Stem Cells / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Histones / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism*
  • Methylation
  • Methyltransferases / metabolism
  • Mice
  • Mice, SCID
  • Signal Transduction


  • Bone Morphogenetic Proteins
  • Histones
  • Methyltransferases

Associated data

  • GEO/GSE15267
  • GEO/GSE19604