Position-Dependent Silencing of Germline Vβ Segments on TCRβ Alleles Containing Preassembled VβDJβCβ1 Genes

The genomic organization of TCR beta loci enables V beta-to-DJ beta 2 rearrangements on alleles with assembled V beta DJ beta C beta 1 genes, which could have deleterious physiologic consequences. To determine whether such V beta rearrangements occur and, if so, how they might be regulated, we analyzed mice with TCR beta alleles containing preassembled functional V beta DJ beta C beta 1 genes. V beta 10 segments were transcribed, rearranged, and expressed in thymocytes when located immediately upstream of a V beta 1DJ beta C beta 1 gene, but not on alleles with a V beta 14DJ beta C beta 1 gene. Germline V beta 10 transcription was silenced in mature alpha beta T cells. This allele-dependent and developmental stage-specific silencing of V beta 10 correlated with increased CpG methylation and decreased histone acetylation over the V beta 10 promoter and coding region. Transcription, rearrangement, and expression of the V beta 4 and V beta 16 segments located upstream of V beta 10 were silenced on alleles containing either V beta DJ beta C beta 1 gene; sequences within V beta 4, V beta 16, and the V beta 4/V beta 16-V beta 10 intergenic region exhibited constitutive high CpG methylation and low histone acetylation. Collectively, our data indicate that the position of V beta segments relative to assembled V beta DJ beta C beta 1 genes influences their rearrangement and suggest that DNA sequences between V beta segments may form boundaries between active and inactive V beta chromatin domains upstream of V beta DJ beta C beta genes. The Journal of Immunology, 2010, 185: 3564-3573.