Combinatorial H3K9acS10ph Histone Modifications in IgH Locus S Regions Target 14-3-3 Adaptors and AID to Specify Antibody Class Switch DNA Recombination

• Published in: Cell reports (Cambridge) Vol. 5; no. 3; pp. 702 - 714
• Main Authors: Li, Guideng, White, Clayton A., Lam, Tonika, Pone, Egest J., Tran, Daniel C., Hayama, Ken L., Zan, Hong, Xu, Zhenming, Casali, Paolo
• Format: Journal Article
• Language: English
• Published: 24.10.2013
• ISSN: 2211-1247
• DOI: 10.1016/j.celrep.2013.09.031

Class switch DNA recombination (CSR) is central to the antibody response, as it changes the immunoglobulin heavy chain (IgH) constant region, thereby diversifying biological effector functions of antibodies. The 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, which display a high affinity for 5’-AGCT-3’ repeats, as recurring 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 showed that histone methyltransferases and acetyltransferases were induced by CD40- or TLR-signaling and catalyzed H3K4me3 and H3K9ac/K14ac histone modifications, which were enriched in S regions but did not specify the S region target of CSR. By contrast, the combinatorial H3K9acS10ph modification specifically marked the S regions set to recombine and directly recruited 14-3-3 adaptors for AID stabilization there. Inhibition of the enzymatic activity of GCN5 and PCAF histone acetyltransferases reduced H3K9acS10ph in S regions, 14-3-3 and AID stabilization, and CSR. Thus, H3K9acS10ph is a histone code that is specifically “written” in S regions and “read” by 14-3-3 adaptors to target AID for CSR as an important biological outcome.