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

EMBO Rep. 2023 Oct 9;24(10):e57032. doi: 10.15252/embr.202357032. Epub 2023 Aug 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation
  • Cellular Senescence / genetics
  • Hematopoiesis
  • Hematopoietic Stem Cells / metabolism
  • Histones* / metabolism
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism

Substances

  • Transcription Factors
  • Histones
  • Nuclear Proteins

Associated data

  • GEO/GSE189836
  • GEO/GSE189834
  • GEO/GSE189835
  • GEO/GSE189832
  • GEO/GSE189833