BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses
BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses
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DOI：
10.15252/embj.2018100293
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发表时间：
2019-04-01
期刊：
影响因子：
11.4
通讯作者：
Ozato, Keiko
中科院分区：
文献类型：
--
作者：
Dey, Anup;Yang, Wenjing;Ozato, Keiko
BRD 4是结合乙酰化组蛋白并调节转录的BET家族蛋白。BET/BRD 4抑制剂阻断血癌生长和炎症，并作为一种新的治疗策略。然而，BRD 4在正常造血和炎症中的生物学作用尚未完全了解。对Brd 4条件性敲除（KO）小鼠的分析表明，BRD 4是造血干细胞扩增和祖细胞发育所需的。然而，BRD 4在巨噬细胞发育和对LPS的炎症反应中发挥有限的作用。ChIP-seq分析表明，尽管其重要性有限，但BRD 4广泛占据巨噬细胞基因组并参与超级增强子（SE）的形成。尽管BRD 4对于癌症中SE的形成至关重要，但巨噬细胞SE并不需要BRD 4，因为KO巨噬细胞会产生替代的、不含BRD 4的SE，以补偿BRD 4的损失。这种机制和其他机制导致巨噬细胞中炎症反应的保留。我们的研究结果说明了BRD 4和可塑性的表观遗传调控的上下文依赖性的作用。
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.