BRD4 指导造血干细胞的发育并调节巨噬细胞的炎症反应。

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

机构信息

Division of Developmental Biology, National Institute of Child Health and Human Development, Bethesda, MD, USA.

The DNA Sequencing and Computational Biology, National Heart, Lung and Blood Institute, Bethesda, MD, USA.

出版信息

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

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.

BRD4 是一种 BET 家族蛋白，可与乙酰化组蛋白结合并调节转录。BET/BRD4 抑制剂可阻断血液癌的生长和炎症，是一种新的治疗策略。然而，BRD4 在正常造血和炎症中的生物学作用尚不完全清楚。对 Brd4 条件性敲除 (KO) 小鼠的分析表明，BRD4 是造血干细胞扩增和祖细胞发育所必需的。然而，BRD4 在巨噬细胞发育和 LPS 诱导的炎症反应中仅发挥有限作用。ChIP-seq 分析表明，尽管 BRD4 的作用有限，但它广泛占据了巨噬细胞基因组，并参与了超级增强子 (SE) 的形成。尽管 BRD4 对癌症中 SE 的形成至关重要，但 BRD4 对于巨噬细胞 SE 并非必需，因为 KO 巨噬细胞形成了替代性的、无 BRD4 的 SE，弥补了 BRD4 的缺失。这种和其他机制导致巨噬细胞中炎症反应得以保留。我们的结果说明了 BRD4 的上下文依赖性作用和表观遗传调控的可塑性。