Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA.
Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
EMBO Rep. 2023 Oct 9;24(10):e57032. doi: 10.15252/embr.202357032. Epub 2023 Aug 31.
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 ) 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 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 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 HSC/HPCs. This study unveils an important role of BRD4 in HSC/HPC function by preventing H3 clipping and suppressing senescence gene expression.
溴结构域蛋白 4（BRD4）在各种髓系恶性肿瘤中过度表达，并具有功能相关性。然而，BRD4 在正常造血中的作用在很大程度上仍然未知。在这里，我们利用诱导型 Brd4 敲除小鼠模型，发现造血系统中 Brd4 的缺失（Brd4 ）会损害造血干细胞（HSC）的自我更新和分化，这与细胞周期停滞和衰老有关。ATAC-seq 分析显示 Brd4 造血干细胞/祖细胞（HSC/HPC）中的染色质可及性增加。使用靶向切割和释放核酸酶（CUT&RUN）测定进行的全基因组作图表明，Brd4 HSC/HPC 中 H3K122ac 和 H3K4me3 的全局富集增加与衰老特异性基因的上调有关。有趣的是，Brd4 缺失会增加被剪辑的 H3（cH3），这与衰老特异性基因的上调相关，并导致衰老的 HSC/HPC 频率更高。BRD4 的重新表达降低了 cH3 水平，并挽救了 Brd4 HSC/HPC 中的衰老率。这项研究揭示了 BRD4 通过防止 H3 剪辑和抑制衰老基因表达在 HSC/HPC 功能中的重要作用。
