BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses

Anup Dey, Wenjing Yang, Anne Gegonne, Akira Nishiyama, Richard Pan, Ryoji Yagi, Alex Grinberg, Fred D. Finkelman, Karl Pfeifer, Jinfang Zhu, Dinah Singer, Jun Zhu, Keiko Ozato

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

BRD4 is a BET family protein that binds acetylated histones and regulates transcription. BET/BRD4 inhibitors block blood cancer growth and inflammation and serve as a new therapeutic strategy. However, the biological role of BRD4 in normal hematopoiesis and inflammation is not fully understood. Analysis of Brd4 conditional knockout (KO) mice showed that BRD4 is required for hematopoietic stem cell expansion and progenitor development. Nevertheless, BRD4 played limited roles in macrophage development and inflammatory response to LPS. ChIP-seq analysis showed that despite its limited importance, BRD4 broadly occupied the macrophage genome and participated in super-enhancer (SE) formation. Although BRD4 is critical for SE formation in cancer, BRD4 was not required for macrophage SEs, as KO macrophages created alternate, BRD4-less SEs that compensated BRD4 loss. This and additional mechanisms led to the retention of inflammatory responses in macrophages. Our results illustrate a context-dependent role of BRD4 and plasticity of epigenetic regulation.

Original languageEnglish
Article numbere100293
JournalEMBO Journal
Volume38
Issue number7
DOIs
StatePublished - 1 Apr 2019
Externally publishedYes

Keywords

  • BRD4
  • LPS
  • hematopoietic stem cells
  • macrophages
  • super-enhancers

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