Chromatin modifications as clues to the regulation of antigen receptor assembly

Abstract

Changes in chromatin structure play a key role in the regulation of the mammalian genome, governing diverse processes including transcription, replication and recombination. In the earliest stages of antigen receptor assembly, D and J segments of the immunoglobulin heavy chain (IgH) and T cell receptor (TCR) beta loci are recombined in B and T cells respectively, while the V segments are not. Distinct distribution patterns of various histone modifications and the nucleosome-remodelling factor Brg1 are found at recombinationally 'active' (DJ) and 'inactive' (V) regions, offering a means independent of transcription or DNAse I hypersensitivity to define chromatin domains at these loci. Within some inactive loci marked by H3-K9 dimethylation, two distinct levels of methylation are found in a non-random, gene-segment specific pattern. Brg1 is not localized to specific sequences, as it is with transcriptional initiation, but rather associates with the entire active locus in a pattern that mirrors acetylation of histone H3. Distinct 'hotspots' of histone H3 dimethylated at lysine 4 are localized at the ends of the active DJ domains of both the IgH and TCRbeta loci, suggesting they may serve as important marks for locus accessibility. The specific patterns of modification imply that the regulation of V(D)J recombination involves recruitment of specific methyltransferases in a localized manner.