Distinct Requirements of CHD4 during B Cell Development and Antibody Response

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

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.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / physiology
  • Cell Differentiation
  • Cell Proliferation*
  • Cells, Cultured
  • Chromatin Assembly and Disassembly
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • Genes, Immunoglobulin Heavy Chain
  • Immunoglobulin Class Switching*
  • Mice
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Mi-2beta protein, mouse
  • DNA Helicases