BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses

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.

HIRA, a DiGeorge Syndrome Candidate Gene, Confers Proper Chromatin Accessibility on HSCs and Supports All Stages of Hematopoiesis

“…The strategy to delete exon 7 was previously used to construct total Hira KO (Roberts et al, 2002). To delete Hira in hematopoietic cells, Hira f/f mice were crossed with mice with Vav-Cre, which disrupts floxed genes in early hematopoietic cells, including HSCs (Aggarwal et al, 2012;Dey et al, 2019;Stadtfeld and Graf, 2005). qRT-PCR data from Hira-KO BM, spleen, and thymus confirmed the loss of exon 7 transcripts, with some residual exon 9 transcripts, as expected ( Figures 1B-1D).…”

“…Conversely, Sox17 is required for fetal, but not adult hematopoiesis (Kim et al, 2007(Kim et al, , 2018. On the other hand, factors such as BRD4 are required for both fetal and adult hematopoiesis (Dey et al, 2019). HIRA apparently belongs to the former group.…”

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

“…As a chronic disease, T2D may cause inflammatory response in different organs or tissues (34). Increasing studies report the critical role of BRD4 in the regulation of inflammatory response, suggesting that BRD4 might be implicated in the pathology of diabetes (35,36). In addition, MMPs, as a marker of degeneration in IVDs, are significantly enhanced in different stresses (13,37).…”

Angioplasty-induced epigenomic remodeling entails BRD4 and EZH2 hierarchical regulations

“…The Brd4 fl/fl mouse line 35 with loxP sites flanking Brd4 exon 3 were kindly provided by Dr. Keiko Ozato from National Institute of Child Health and Human (NICHD). The smooth muscle lineagespecific, tamoxifen-inducible Cre strain (Myh11-CreER T2 ) was purchased from The Jackson Laboratory.…”

“…The smooth muscle lineagespecific, tamoxifen-inducible Cre strain (Myh11-CreER T2 ) was purchased from The Jackson Laboratory. These two strains were crossed, and the offsprings carrying Brd4 fl/fl and/or Myh11-CreER T2 were selected through RT-PCR genotyping as previously described 35 . Genotyping PCR primers are provided in Table S3.…”