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BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses
Author(s) -
Dey Anup,
Yang Wenjing,
Gegonne Anne,
Nishiyama Akira,
Pan Richard,
Yagi Ryoji,
Grinberg Alex,
Finkelman Fred D,
Pfeifer Karl,
Zhu Jinfang,
Singer Dinah,
Zhu Jun,
Ozato Keiko
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100293
Subject(s) - biology , haematopoiesis , stem cell , hematopoietic stem cell , macrophage , microbiology and biotechnology , inflammation , immunology , cancer research , genetics , in vitro
BRD 4 is a BET family protein that binds acetylated histones and regulates transcription. BET / BRD 4 inhibitors block blood cancer growth and inflammation and serve as a new therapeutic strategy. However, the biological role of BRD 4 in normal hematopoiesis and inflammation is not fully understood. Analysis of Brd4 conditional knockout ( KO ) mice showed that BRD 4 is required for hematopoietic stem cell expansion and progenitor development. Nevertheless, BRD 4 played limited roles in macrophage development and inflammatory response to LPS . Ch IP ‐seq analysis showed that despite its limited importance, BRD 4 broadly occupied the macrophage genome and participated in super‐enhancer ( SE ) formation. Although BRD 4 is critical for SE formation in cancer, BRD 4 was not required for macrophage SE s, as KO macrophages created alternate, BRD 4‐less SE s that compensated BRD 4 loss. This and additional mechanisms led to the retention of inflammatory responses in macrophages. Our results illustrate a context‐dependent role of BRD 4 and plasticity of epigenetic regulation.