Deletion of germline promoter PD beta 1 from the TCR beta locus causes hypermethylation that impairs D beta 1 recombination by multiple mechanisms.
The role of the germline transcriptional promoter, PD beta 1, in V(D)J recombination at the T cell receptor beta locus was investigated. Deletion of PD beta 1 caused reduced germline transcription and DNA hypermethylation in the Dbeta1-J beta 1 region and decreased D beta 1 rearrangement. Analyses of methylation levels surrounding recombination signal sequences (RSS) before, during, and after recombination revealed that under physiological conditions cleavage of hypomethylated alleles was preferred over hypermethylated alleles. Methylation of a specific CpG site within the heptamer of the 3' D beta 1 RSS was incompatible with cleavage by the V(D)J recombinase. These findings suggest that methylation can regulate V(D)J recombination both at a general level by influencing regional chromatin accessibility and specifically by blocking RSS recognition or cleavage by the V(D)J recombinase.
Whitehurst
C E
CE
Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Schlissel
M S
MS
Chen
J
J
D000818:Animals; D019175:DNA Methylation; D004254:DNA Nucleotidyltransferases / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology; D011995:Recombination, Genetic; D045567:VDJ Recombinases
D016693:Receptors, Antigen, T-Cell, alpha-beta; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases