Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes

Cell Rep. 2014 Oct 9;9(1):234-247. doi: 10.1016/j.celrep.2014.08.055. Epub 2014 Sep 26.


Transcription factors and chromatin-remodeling complexes are key determinants of embryonic stem cell (ESC) identity. Here, we demonstrate that BRD4, a member of the bromodomain and extraterminal domain (BET) family of epigenetic readers, regulates the self-renewal ability and pluripotency of ESCs. BRD4 inhibition resulted in induction of epithelial-to-mesenchymal transition (EMT) markers and commitment to the neuroectodermal lineage while reducing the ESC multidifferentiation capacity in teratoma assays. BRD4 maintains transcription of core stem cell genes such as OCT4 and PRDM14 by occupying their super-enhancers (SEs), large clusters of regulatory elements, and recruiting to them Mediator and CDK9, the catalytic subunit of the positive transcription elongation factor b (P-TEFb), to allow Pol-II-dependent productive elongation. Our study describes a mechanism of regulation of ESC identity that could be applied to improve the efficiency of ESC differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / physiology*
  • Gene Expression Regulation, Developmental
  • Humans
  • Mice
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism
  • Pluripotent Stem Cells / physiology*
  • Positive Transcriptional Elongation Factor B / genetics
  • Positive Transcriptional Elongation Factor B / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transcription, Genetic


  • BRD4 protein, human
  • Brd4 protein, mouse
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Positive Transcriptional Elongation Factor B

Associated data

  • GEO/GSE60171