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

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 (Brd4D/D) in the hematopoietic sys-tem impairs hematopoietic stem cell (HSC) self-renewal and differ-entiation, which associates with cell cycle arrest and senescence. ATAC-seq analysis shows increased chromatin accessibility in Brd4D/D 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 Brd4D/D HSC/HPCs is associated with the upregulation of senescence-specific genes. Interestingly, Brd4 deletion increases clipped H3 (cH3) which corre-lates 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 Brd4D/D HSC/HPCs. This study unveils an important role of BRD4 in HSC/HPC function by preventing H3 clipping and suppressing senescence gene expression.

Automated summary

This study reveals that deletion of Brd4 affects the self-renewal and differentiation of HSCs, leading to cell cycle arrest and senescence. The deletion of Brd4 results in increased chromatin accessibility and upregulation of senescence-specific genes. However, re-expression of BRD4 can rescue these effects by reducing H3 clipping and suppressing senescence gene expression.