Combinatorial H3K9acS10ph histone modification in igh locus s regions targets 14-3-3 adaptors and aid to specify antibody class-switch DNA recombination

Guideng Li, Clayton A. White, Tonika Lam, Egest J. Pone, Daniel C. Tran, Ken L. Hayama, Hong Zan, Zhenming Xu, Paolo Casali

Research output: Contribution to journalArticle

30 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)702-714
Number of pages13
JournalCell Reports
Volume5
Issue number3
DOIs
StatePublished - Oct 28 2013

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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