Loss of BRD4 induces cell senescence in HSC/HPCs by deregulating histone H3 clipping

Abstract

Bromodomain‐containing protein 4 (BRD4) is overexpressed and functionally implicated in various myeloid malignancies. However, the role of BRD4 in normal hematopoiesis remains largely unknown. Here, utilizing an inducible Brd4 knockout mouse model, we find that deletion of Brd4 ( Brd4 Δ/Δ ) in the hematopoietic system impairs hematopoietic stem cell (HSC) self‐renewal and differentiation, which associates with cell cycle arrest and senescence. ATAC‐seq analysis shows increased chromatin accessibility in Brd4 Δ/Δ hematopoietic stem/progenitor cells (HSC/HPCs). Genome‐wide mapping with cleavage under target and release using nuclease (CUT&RUN) assays demonstrate that increased global enrichment of H3K122ac and H3K4me3 in Brd4 Δ/Δ HSC/HPCs is associated with the upregulation of senescence‐specific genes. Interestingly, Brd4 deletion increases clipped H3 (cH3) which correlates with the upregulation of senescence‐specific genes and results in a higher frequency of senescent HSC/HPCs. Re‐expression of BRD4 reduces cH3 levels and rescues the senescence rate in Brd4 Δ/Δ HSC/HPCs. This study unveils an important role of BRD4 in HSC/HPC function by preventing H3 clipping and suppressing senescence gene expression. image BRD4 is required for normal HSC functions by suppressing cell senescence and regulating the cell cycle. Mechanistically, BRD4 regulates chromatin accessibility and prevents H3.3 clipping to regulate senescence‐specific gene expression. Loss of Brd4 induces cell senescence and cell cycle arrest, leading to the impairment of HSC function. BRD4 maintains chromatin accessibility and regulates the expression of genes critical for HSC functions. Brd4 deletion induces histone H3 clipping and upregulates senescence‐specific genes. Re‐expression of Brd4 reduces cH3 levels and senescence of Brd4 Δ/Δ HSC/HPCs.