Facilitators and Impediments of the Pluripotency Reprogramming Factors' Initial Engagement With the Genome

Cell. 2012 Nov 21;151(5):994-1004. doi: 10.1016/j.cell.2012.09.045. Epub 2012 Nov 15.

Abstract

The ectopic expression of transcription factors can reprogram cell fate, yet it is unknown how the initial binding of factors to the genome relates functionally to the binding seen in the minority of cells that become reprogrammed. We report a map of Oct4, Sox2, Klf4, and c-Myc (O, S, K, and M) on the human genome during the first 48 hr of reprogramming fibroblasts to pluripotency. Three striking aspects of the initial chromatin binding events include an unexpected role for c-Myc in facilitating OSK chromatin engagement, the primacy of O, S, and K as pioneer factors at enhancers of genes that promote reprogramming, and megabase-scale chromatin domains spanned by H3K9me3, including many genes required for pluripotency, that prevent initial OSKM binding and impede the efficiency of reprogramming. We find diverse aspects of initial factor binding that must be overcome in the minority of cells that become reprogrammed.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cellular Reprogramming*
  • Chromatin / metabolism
  • Embryonic Stem Cells / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Gene Expression
  • Genome, Human*
  • Histone Code
  • Humans
  • Kruppel-Like Transcription Factors / metabolism
  • Models, Molecular
  • Octamer Transcription Factor-3 / metabolism
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism
  • SOXB1 Transcription Factors / metabolism

Substances

  • Chromatin
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • MYC protein, human
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • Proto-Oncogene Proteins c-myc
  • SOX2 protein, human
  • SOXB1 Transcription Factors

Associated data

  • GEO/GSE36570