Combinatorial H3K9acS10ph histone modification in IgH locus S regions targets 14-3-3 adaptors and AID to specify antibody class-switch DNA recombination

Cell Rep. 2013 Nov 14;5(3):702-714. doi: 10.1016/j.celrep.2013.09.031. Epub 2013 Oct 24.

Abstract

Class-switch DNA recombination (CSR) is central to the antibody response, in that it changes the immunoglobulin heavy chain (IgH) constant region, thereby diversifying biological effector functions of antibodies. The activation-induced cytidine deaminase (AID)-centered CSR machinery excises and rejoins DNA between an upstream (donor) and a downstream (acceptor) S region, which precede the respective constant region DNA. AID is stabilized on S regions by 14-3-3 adaptors. These adaptors display a high affinity for 5'-AGCT-3' repeats, which recur in all S regions. However, how 14-3-3, AID, and the CSR machinery target exclusively the donor and acceptor S regions is poorly understood. Here, we show that histone methyltransferases and acetyltransferases are induced by CD40 or Toll-like receptor signaling and catalyze H3K4me3 and H3K9ac/K14ac histone modifications, which are enriched in S regions but do not specify the S region targets of CSR. By contrast, the combinatorial H3K9acS10ph modification specifically marks the S regions set to recombine and directly recruits 14-3-3 adaptors for AID stabilization there. Inhibition of the enzymatic activity of GCN5 and PCAF histone acetyltransferases reduces H3K9acS10ph in S regions, 14-3-3 and AID stabilization, and CSR. Thus, H3K9acS10ph is a histone code that is "written" specifically in S regions and is "read" by 14-3-3 adaptors to target AID for CSR as an important biological outcome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 14-3-3 Proteins / genetics
  • 14-3-3 Proteins / metabolism*
  • Animals
  • Cytidine Deaminase / genetics*
  • Cytidine Deaminase / immunology
  • DNA / genetics*
  • DNA / immunology
  • Histones / genetics*
  • Histones / immunology
  • Immunoglobulin Class Switching / genetics*
  • Immunoglobulin Heavy Chains / genetics*
  • Immunoglobulin Heavy Chains / immunology
  • Immunoglobulin Variable Region / genetics
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Recombination, Genetic

Substances

  • 14-3-3 Proteins
  • Histones
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • DNA
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase