BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses

被引：107

作者：

Dey, Anup ^{[1
]}

Yang, Wenjing ^{[2
]}

Gegonne, Anne ^{[3
]}

Nishiyama, Akira ^{[1
,6
]}

Pan, Richard ^{[1
]}

Yagi, Ryoji ^{[4
,7
]}

Grinberg, Alex ^{[1
]}

Finkelman, Fred D. ^{[5
]}

Pfeifer, Karl ^{[1
]}

Zhu, Jinfang ^{[4
]}

Singer, Dinah ^{[3
]}

Zhu, Jun ^{[2
]}

Ozato, Keiko ^{[1
]}

机构：

[1] NICHHD, Div Dev Biol, Bethesda, MD 20892 USA

[2] NHLBI, DNA Sequencing & Computat Biol, Bldg 10, Bethesda, MD 20892 USA

[3] NCI, Expt Immunol Branch, Bldg 10, Bethesda, MD 20892 USA

[4] NIAID, Lab Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[5] Cincinnati Childrens Hosp, Dept Pediat, Cincinnati, OH USA

[6] Yokohama City Univ, Grad Sch Med, Dept Immunol, Yokohama, Kanagawa, Japan

[7] Chiba Univ, Grad Sch Med, Dept Immunol, Chiba, Japan

来源：

EMBO JOURNAL | 2019年 / 38卷 / 07期

关键词：

BRD4; hematopoietic stem cells; LPS; macrophages; super-enhancers; BROMODOMAIN PROTEIN BRD4; SELECTIVE-INHIBITION; GENE-EXPRESSION; SUPER-ENHANCERS; BET PROTEIN; P-TEFB; TRANSCRIPTION; ELONGATION; DOMAIN; PHOSPHORYLATION;

D O I：

10.15252/embj.2018100293

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：17

共 46 条

[31] Fast and accurate short read alignment with Burrows-Wheeler transform [J].