The BET Family Member BRD4 Interacts With OCT4 and Regulates Pluripotency Gene Expression

Stem Cell Reports. 2015 Mar 10;4(3):390-403. doi: 10.1016/j.stemcr.2015.01.012. Epub 2015 Feb 12.

Abstract

Embryonic stem cell (ESC) pluripotency is controlled by defined transcription factors. During cellular differentiation, ESCs undergo a global epigenetic reprogramming. Female ESCs exemplify this process as one of the two X-chromosomes is globally silenced during X chromosome inactivation (XCI) to balance the X-linked gene disparity with XY males. The pluripotent factor OCT4 regulates XCI by triggering X chromosome pairing and counting. OCT4 directly binds Xite and Tsix, which encode two long noncoding RNAs (lncRNAs) that suppress the silencer lncRNA, Xist. To control its activity as a master regulator in pluripotency and XCI, OCT4 must have chromatin protein partners. Here we show that BRD4, a member of the BET protein subfamily, interacts with OCT4. BRD4 occupies the regulatory regions of pluripotent genes and the lncRNAs of XCI. BET inhibition or depletion of BRD4 reduces the expression of many pluripotent genes and shifts cellular fate showing that BRD4 is pivotal for transcription in ESCs.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Line
  • Cell Self Renewal / genetics*
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism*
  • Epigenesis, Genetic
  • Female
  • Gene Expression
  • Gene Expression Regulation, Developmental*
  • Gene Silencing
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Male
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism*
  • Positive Transcriptional Elongation Factor B / metabolism
  • Protein Binding
  • RNA, Long Noncoding / genetics
  • Regulatory Sequences, Nucleic Acid
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • X Chromosome Inactivation / genetics

Substances

  • Brd4 protein, mouse
  • Heat-Shock Proteins
  • Hexim1 protein, mouse
  • Nuclear Proteins
  • Octamer Transcription Factor-3
  • RNA, Long Noncoding
  • SESN3 protein, mouse
  • Transcription Factors
  • XIST non-coding RNA
  • Positive Transcriptional Elongation Factor B