The Chromatin Reader ZMYND8 Regulates Igh Enhancers to Promote Immunoglobulin Class Switch Recombination

Mol Cell. 2018 Nov 15;72(4):636-649.e8. doi: 10.1016/j.molcel.2018.08.042. Epub 2018 Oct 4.


Class switch recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3' Igh super-enhancer, 3' regulatory region (3'RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here, we identify the chromatin reader ZMYND8 as an essential regulator of the 3'RR. In B cells, ZMYND8 binds promoters and super-enhancers, including the Igh enhancers. ZMYND8 controls the 3'RR activity by modulating the enhancer transcriptional status. In its absence, there is increased 3'RR polymerase loading and decreased acceptor region transcription and CSR. In addition to CSR, ZMYND8 deficiency impairs somatic hypermutation (SHM) of Igh, which is also dependent on the 3'RR. Thus, ZMYND8 controls Igh diversification in mature B lymphocytes by regulating the activity of the 3' Igh super-enhancer.

Keywords: 3′ regulatory region; Igh super-enhancer; ZMYND8; class switch recombination; germline transcription; somatic hypermutation.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes
  • Cell Line
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly / genetics*
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism
  • DNA / genetics
  • Enhancer Elements, Genetic
  • Gene Rearrangement
  • Humans
  • Immunoglobulin Class Switching / genetics*
  • Immunoglobulin Heavy Chains / genetics*
  • MYND Domains
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic
  • Regulatory Sequences, Nucleic Acid
  • Somatic Hypermutation, Immunoglobulin / genetics
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism


  • Chromatin
  • Immunoglobulin Heavy Chains
  • Tumor Suppressor Proteins
  • ZMYND8 protein, human
  • DNA
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase