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EMBO J. 2019 Apr 1;38(7). pii: e100293. doi: 10.15252/embj.2018100293. Epub 2019 Mar 6.

BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses.

Author information

1
Division of Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD, USA.
2
The DNA Sequencing and Computational Biology, National Heart, Lung and Blood Institute, Bethesda, MD, USA.
3
Experimental Immunology Branch, National Cancer Institute, Bethesda, MD, USA.
4
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
5
Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH, USA.
6
Division of Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD, USA ozatok@nih.gov.

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.

KEYWORDS:

LPS ; BRD4; hematopoietic stem cells; macrophages; super‐enhancers

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