Abstract
Author SummaryDNA methylation at CpG dinucleotides is implicated in the regulation of gene expression in mammals. However, the regulation of DNA methylation itself is less clear despite recent advances in identifying enzymes that add or remove methyl groups. We have investigated the dynamics of DNA methylation during genome rearrangements that assemble antigen receptor genes in developing B lymphocytes to determine whether methylation status correlates with rearrangement potential. Two recombination events generate immunoglobulin heavy chain (IgH) genes. The first step brings together diversity (DH) and joining (JH) gene segments to produce DJH junctions. We show that both gene segments are methylated prior to rearrangement, whereas the DJH product is demethylated. DJH junctional demethylation is tissue-specific and requires an enhancer, Eμ, located within the IgH locus. The latter observations indicate that localized demethylation of the DJH junction occurs after the first recombination step and thus does not guide this first step of IgH gene assembly. Our working hypothesis is that recombination induces demethylation of recombinant product and may mark the junction for the second step of IgH rearrangement, juxtaposition of variable (VH) gene segments to rearranged DJH products to produce fully recombined V(D)J alleles.
Highlights
Tissue-specific gene expression requires multiple epigenetic changes
The region encompassing the IgH joining region (JH) gene segments is marked by the highest levels of histone acetylation and histone H3 trimethylation at lysine 4 (H3K4me3) (Figure 1) [23,24,25]
We found that unrearranged DFL16.1, DSP, and JH regions were methylated, while Em region was demethylated (Figure 4A) as seen in RAG2-deficient pro-B cells
Summary
Tissue-specific gene expression requires multiple epigenetic changes. These include nuclear location, chromatin remodeling, covalent histone modifications, and DNA methylation [1,2,3,4]. Most studies of CpG methylation vis-a-vis transcription have focused on gene promoters, those that contain CpG islands (CGI). Such promoters are typically un-methylated and are transcriptionally active; methylated CGI promoters are usually transcriptionally silent. The advent of whole genome CpG mapping has drawn attention to possible functions of CpG methylation within gene bodies [8,9] Proposed functions for such CpGs include transcription elongation and the regulation of splicing. The lack of a coherent picture for the role of CpG methylation in non-CGI contexts indicates an ongoing need for analysis of CpG methylation, in tissue-specific genes that lack CGIs
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