Distinct Requirements of CHD4 during B Cell Development and Antibody Response

• Published in: Cell reports (Cambridge) Vol. 27; no. 5; pp. 1472 - 1486.e5
• Main Authors: Yen, Wei-Feng, Sharma, Rahul, Cols, Montserrat, Lau, Colleen M., Chaudhry, Ashutosh, Chowdhury, Priyanka, Yewdell, William T., Vaidyanathan, Bharat, Sun, Amy, Coffre, Maryaline, Pucella, Joseph N., Chen, Chun-Chin, Jasin, Maria, Sun, Joseph C., Rudensky, Alexander Y., Koralov, Sergei B., Chaudhuri, Jayanta
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.04.2019; Elsevier
• Subjects: AID; Animals; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - physiology; Cell Differentiation; Cell Proliferation; Cells, Cultured; CHD4; Chromatin Assembly and Disassembly; chromatin remodeling; class switch recombination; DNA Helicases - genetics; DNA Helicases - metabolism; Genes, Immunoglobulin Heavy Chain; germinal centers; H3K9me3; Immunoglobulin Class Switching; Mice; NuRD complex; p53; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; H3K9me3; germinal centers; chromatin remodeling; CHD4; AID; class switch recombination; NuRD complex; p53
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.04.011

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. [Display omitted] •CHD4 is essential for early B cell development•Naive, mature B cells can sustain loss of CHD4•CHD4 represses p53 expression and promotes B cell proliferation•Loss of CHD4 influences recruitment of AID to the Igh locus and impairs CSR Yen et al. demonstrate that CHD4, a component of the NuRD remodeling complex, is essential for early B cell development, represses p53 expression in mature B cells, and influences the recruitment of AID to DNA during class switch recombination.