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 (Brd4 ) in the hemato...

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Bibliographic Details
Published in:EMBO reports 2023-10, Vol.24 (10), p.e57032
Main Authors: Yang, Hui, Sui, Pinpin, Guo, Ying, Chen, Shi, Maloof, Marie E, Ge, Guo, Nihozeko, Francine, Delma, Caroline R, Zhu, Ganqian, Zhang, Peng, Ye, Zhenqing, Medina, Edward A, Ayad, Nagi G, Mesa, Ruben, Nimer, Stephen D, Chiang, Cheng-Ming, Xu, Mingjiang, Chen, Yidong, Yang, Feng-Chun
Format: Article
Language:English
Subjects:
Accessibility
Animal models
Animals
Cell cycle
Cell Differentiation
Cellular Senescence - genetics
Chromatin
Deletion
Deregulation
Gene expression
Gene mapping
Genes
Genetic diversity
Genomes
Hematopoiesis
Hematopoietic stem cells
Hematopoietic Stem Cells - metabolism
Hematopoietic system
Hemopoiesis
Histone H3
Histones
Histones - metabolism
Malignancy
Mice
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Nuclease
Progenitor cells
Senescence
Stem cells
Transcription Factors - genetics
Transcription Factors - metabolism
Up-regulation
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Summary: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.
ISSN:1469-221X
1469-3178
1469-3178
DOI:10.15252/embr.202357032