Histone modifications associated with somatic hypermutation.
A number of modified histones, including acetylated H3 and H4 and phosphorylated H2AX (gammaH2AX), are associated with V(D)J recombination and class switch recombination (CSR). In contrast, little is known concerning the chromatin modifications associated with somatic hypermutation (SHM) in vivo. Here, we report that several modifications--including histone acetylation and H3-lysine 4 methylation--fail to demarcate an actively hypermutating immunoglobulin (Ig) locus or to correlate spatially with SHM within Ig loci. Furthermore, no obvious association between SHM and gammaH2AX could be detected. Instead, we find that the phosphorylated form of histone H2B (H2B(Ser14P)) correlates tightly with SHM and CSR. Phosphorylation of H2B within Ig variable and switch regions requires AID and may be mediated by the histone kinase Mst1. These findings indicate that SHM and CSR trigger distinct DNA damage responses and identify a novel histone modification pattern for SHM consisting of H2B(Ser14P) in the absence of gammaH2AX.
Odegard
Valerie H
VH
Section of Immunobiology, Yale University School of Medicine, Box 208011, New Haven, Connecticut 06520, USA.
Kim
Sean T
ST
Anderson
Shannon M
SM
Shlomchik
Mark J
MJ
Schatz
David G
DG
D000107:Acetylation; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D004249:DNA Damage; D019175:DNA Methylation; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D017578:Immunoglobulin Class Switching; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000378:metabolism; D007146:Immunoglobulin lambda-Chains / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D027041:Somatic Hypermutation, Immunoglobulin; D000099317:Hippo Kinases
D002843:Chromatin; D006657:Histones; D007147:Immunoglobulin Light Chains; D007146:Immunoglobulin lambda-Chains; D017346:Protein Serine-Threonine Kinases; C475961:gamma-H2AX protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases