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

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

doi:10.15252/embr.202357032

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

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

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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 (Brd4^Δ/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 Brd4^Δ/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 Brd4^Δ/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 Brd4^Δ/Δ HSC/HPCs. This study unveils an important role of BRD4 in HSC/HPC function by preventing H3 clipping and suppressing senescence gene expression.

Original language	English (US)
Article number	e57032
Journal	EMBO Reports
Volume	24
Issue number	10
DOIs	https://doi.org/10.15252/embr.202357032
State	Published - Oct 9 2023

Keywords

Brd4
hematopoiesis
histone clipping
senescence

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Genetics

Access to Document

10.15252/embr.202357032

Cite this

Yang, H., Sui, P., Guo, Y., Chen, S., Maloof, M. E., Ge, G., Nihozeko, F., Delma, C. R., Zhu, G., Zhang, P., Ye, Z., Medina, E. A., Ayad, N. G., Mesa, R., Nimer, S. D., Chiang, C. M., Xu, M., Chen, Y., & Yang, F. C. (2023). Loss of BRD4 induces cell senescence in HSC/HPCs by deregulating histone H3 clipping. EMBO Reports, 24(10), Article e57032. https://doi.org/10.15252/embr.202357032

@article{d2eada0320c14ff5b302628c19dca3a8,

title = "Loss of BRD4 induces cell senescence in HSC/HPCs by deregulating histone H3 clipping",

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",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Authors.",

year = "2023",

month = oct,

day = "9",

doi = "10.15252/embr.202357032",

language = "English (US)",

volume = "24",

journal = "EMBO Reports",

issn = "1469-221X",

publisher = "Nature Publishing Group",

number = "10",

}

TY - JOUR

T1 - Loss of BRD4 induces cell senescence in HSC/HPCs by deregulating histone H3 clipping

AU - Yang, Hui

AU - Sui, Pinpin

AU - Guo, Ying

AU - Chen, Shi

AU - Maloof, Marie E.

AU - Ge, Guo

AU - Nihozeko, Francine

AU - Delma, Caroline R.

AU - Zhu, Ganqian

AU - Zhang, Peng

AU - Ye, Zhenqing

AU - Medina, Edward A.

AU - Ayad, Nagi G.

AU - Mesa, Ruben

AU - Nimer, Stephen D.

AU - Chiang, Cheng Ming

AU - Xu, Mingjiang

AU - Chen, Yidong

AU - Yang, Feng Chun

PY - 2023/10/9

Y1 - 2023/10/9

N2 - 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.

AB - 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.

KW - Brd4

KW - hematopoiesis

KW - histone clipping

KW - senescence

UR - http://www.scopus.com/inward/record.url?scp=85169314299&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85169314299&partnerID=8YFLogxK

U2 - 10.15252/embr.202357032

DO - 10.15252/embr.202357032

M3 - Article

C2 - 37650863

AN - SCOPUS:85169314299

SN - 1469-221X

VL - 24

JO - EMBO Reports

JF - EMBO Reports

IS - 10

M1 - e57032

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this