2. Academic Validation
  3. 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 Rep. 2023 Aug 31;e57032. doi: 10.15252/embr.202357032.
Hui Yang # 1,  Pinpin Sui # 1,  Ying Guo # 1,  Shi Chen 2,  Marie E Maloof 3,  Guo Ge 1,  Francine Nihozeko 1,  Caroline R Delma 4,  Ganqian Zhu 2,  Peng Zhang 1,  Zhenqing Ye 5 6,  Edward A Medina 4,  Nagi G Ayad 7,  Ruben Mesa 8,  Stephen D Nimer 3,  Cheng-Ming Chiang 9 10 11,  Mingjiang Xu 2 8,  Yidong Chen 5 6,  Feng-Chun Yang 1 8
Affiliations

Affiliations

  • 1 Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 2 Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 3 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 4 Department of Pathology and Laboratory Medicine, Division of Hematopathology, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 5 Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 6 Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 7 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
  • 8 Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, USA.
  • 9 Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 10 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 11 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • # Contributed equally.
PMID: 37650863 DOI: 10.15252/embr.202357032
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.

Keywords

Brd4; hematopoiesis; histone clipping; senescence.

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