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Cell Rep. 2019 Apr 30;27(5):1472-1486.e5. doi: 10.1016/j.celrep.2019.04.011.

Distinct Requirements of CHD4 during B Cell Development and Antibody Response.

Author information

1
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Biochemistry, Cellular and Molecular Biology Program, Weill Graduate School of Medical Sciences, New York, NY, USA.
2
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
4
Department of Pathology, New York University School of Medicine, New York, NY, USA.
5
Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY, USA.
6
Biochemistry, Cellular and Molecular Biology Program, Weill Graduate School of Medical Sciences, New York, NY, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7
Biochemistry, Cellular and Molecular Biology Program, Weill Graduate School of Medical Sciences, New York, NY, USA; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
8
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY, USA.
9
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY, USA; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
10
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY, USA. Electronic address: chaudhuj@mskcc.org.

Abstract

The immunoglobulin heavy chain (Igh) locus features a dynamic chromatin landscape to promote class switch recombination (CSR), yet the mechanisms that regulate this landscape remain poorly understood. CHD4, a component of the chromatin remodeling NuRD complex, directly binds H3K9me3, an epigenetic mark present at the Igh locus during CSR. We find that CHD4 is essential for early B cell development but is dispensable for the homeostatic maintenance of mature, naive B cells. However, loss of CHD4 in mature B cells impairs CSR because of suboptimal targeting of AID to the Igh locus. Additionally, we find that CHD4 represses p53 expression to promote B cell proliferation. This work reveals distinct roles for CHD4 in B cell development and CSR and links the H3K9me3 epigenetic mark with AID recruitment to the Igh locus.

KEYWORDS:

AID; CHD4; H3K9me3; NuRD complex; chromatin remodeling; class switch recombination; germinal centers; p53

PMID:
31042474
DOI:
10.1016/j.celrep.2019.04.011
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