BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses

Abstract BRD4is a BET family protein that binds acetylated histones and regulates transcription. BET/ BRD4inhibitors block blood cancergrowth and inflammation and serve as a new therapeutic strategy. However, the biological role of BRD4in normal hematopoiesis and inflammation is not fully understood. Analysis of Brd4conditional knockout (KO) mice showed that BRD4is required for hematopoietic stem cell expansion and progenitor development. Nevertheless, BRD4played limited roles in macrophage development and inflammatory response to LPS. ChIP‐seq analysis showed that despite its limited importance, BRD4broadly occupied the macrophage genome and participated in super‐enhancer(SE) formation. Although BRD4is critical for SE formation in cancer, BRD4was not required for macrophage SEs, as KO macrophages created alternate, BRD4‐less SEs that compensated BRD4loss. This and additional mechanisms led to the retention of inflammatory responses in macrophages. Our results illustrate a context‐dependent role of BRD4and plasticity of epigenetic regulation.