title: Combinatorial H3K9acS10ph histone modification in IgH locus S regions targets 14-3-3 adaptors and AID to specify antibody class-switch DNA recombination.
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.
authors.affiliation: Institute for Immunology and School of Medicine, University of California, Irvine, 3028 Hewitt Hall, Irvine, CA 92697-4120, USA.
authors.forename: Guideng
authors.initials: G
authors.lastname: Li
authors.affiliation: Institute for Immunology and School of Medicine, University of California, Irvine, 3028 Hewitt Hall, Irvine, CA 92697-4120, USA.
authors.forename: Clayton A
authors.initials: CA
authors.lastname: White
authors.affiliation: Institute for Immunology and School of Medicine, University of California, Irvine, 3028 Hewitt Hall, Irvine, CA 92697-4120, USA.|Department of Microbiology and Immunology, School of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Tonika
authors.initials: T
authors.lastname: Lam
authors.affiliation: Institute for Immunology and School of Medicine, University of California, Irvine, 3028 Hewitt Hall, Irvine, CA 92697-4120, USA.
authors.forename: Egest J
authors.initials: EJ
authors.lastname: Pone
authors.affiliation: Institute for Immunology and School of Medicine, University of California, Irvine, 3028 Hewitt Hall, Irvine, CA 92697-4120, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Tran
authors.affiliation: Institute for Immunology and School of Medicine, University of California, Irvine, 3028 Hewitt Hall, Irvine, CA 92697-4120, USA.
authors.forename: Ken L
authors.initials: KL
authors.lastname: Hayama
authors.affiliation: Institute for Immunology and School of Medicine, University of California, Irvine, 3028 Hewitt Hall, Irvine, CA 92697-4120, USA.|Department of Microbiology and Immunology, School of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zan
authors.affiliation: Institute for Immunology and School of Medicine, University of California, Irvine, 3028 Hewitt Hall, Irvine, CA 92697-4120, USA.|Department of Microbiology and Immunology, School of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Institute for Immunology and School of Medicine, University of California, Irvine, 3028 Hewitt Hall, Irvine, CA 92697-4120, USA.|Department of Microbiology and Immunology, School of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Casali
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003564:Cytidine Deaminase / Q000235:genetics* / Q000276:immunology; D004247:DNA / Q000235:genetics* / Q000276:immunology; D006657:Histones / Q000235:genetics* / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics* / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011995:Recombination, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D048948:14-3-3 Proteins; D006657:Histones; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D004247:DNA; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase