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

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

EMBO reports (2023-08-31)

Hui Yang, Pinpin Sui, Ying Guo, Shi Chen, Marie E Maloof, Guo Ge, Francine Nihozeko, Caroline R Delma, Ganqian Zhu, Peng Zhang, Zhenqing Ye, Edward A Medina, Nagi G Ayad, Ruben Mesa, Stephen D Nimer, Cheng-Ming Chiang, Mingjiang Xu, Yidong Chen, Feng-Chun Yang

PMID37650863

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 (Brd4Δ/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 Brd4Δ/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 Brd4Δ/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 Brd4Δ/Δ HSC/HPCs. This study unveils an important role of BRD4 in HSC/HPC function by preventing H3 clipping and suppressing senescence gene expression.

MATERIALS

Product Number

Brand

Product Description

219372

Sigma-Aldrich

Cathepsin G Inhibitor I, The Cathepsin G Inhibitor I, also referenced under CAS 429676-93-7, controls the biological activity of Cathepsin G. This small molecule/inhibitor is primarily used for Protease Inhibitors applications.

219421

Sigma-Aldrich

Cathepsin L Inhibitor I, The Cathepsin L Inhibitor I, also referenced under CAS 108005-94-3, controls the biological activity of Cathepsin L. This small molecule/inhibitor is primarily used for Protease Inhibitors applications.