κ chain monoallelic demethylation and the establishment of allelic exclusion

Abstract

Allelic exclusion in light-chain synthesis is thought to result from a feedback mechanism by which the expression of a functional light chain on the surface of the B cell leads to an intracellular signal that down-regulates the V(D)J recombinase, thus precluding rearrangement of the other allele. Whereas such a feedback mechanism clearly plays a role in the maintenance of allelic exclusion, here we provide evidence suggesting that the initial establishment of allelic exclusion involves differential availability of the two alleles for rearrangement. Analysis of + B-cell populations and of individual + B cells that have rearranged only one allele demonstrates that in these cells, critical sites on the rearranged allele are unmethylated, whereas the nonrearranged allele remains methylated. This pattern is apparently generated by demethylation that is initiated at the small pre-B cell stage, on a single allele, in a process that occurs prior to rearrangement and requires the presence in cis of both the intronic and 3 enhancers. Taken together with data demonstrating that undermethylation is required for rearrangement, these results indicate that demethylation may actually underly the process of allelic exclusion by directing the initial choice of a single allele for rearrangement.

Variability and Exclusion in Host and Parasite: Epigenetic Regulation of Ig and var Expression

“…However, while termination of the rearrangement process depends on negative feedback generated by signaling of pre-and B cell membrane receptors, the mutually exclusive manner of expression at the var gene family relies entirely on noncoding elements of the P. falciparum genome. Moreover, while DNA-demethylation precedes Ig rearrangement and is essential for the rearrangement to take place (1,2,14), methylation patterns are largely indistinguishable between active and inactive var genes, although subtle differences may still exist (6). This is in agreement with the highly reversible nature of the var decision, which precludes long-term modifications such as DNA demethylation.…”

“…Allelic exclusion is controlled at the V(D)J rearrangement level by initially restricting recombination to only one allele in each cell. The above-described choices seem to be achieved through monoallelic epigenetic changes (1)(2)(3)(4).…”

TCRβ Allelic Exclusion in Dynamical Models of V(D)J Recombination Based on Allele Independence

“…These models support the notion that V(D)J recombination initiates at one allele at a time due to a specific yet ill-defined molecular control(s) (8)(9)(10) or as the result of a stochastic, low-probability onset (11,12). Whatever the cause, a VDJ + outcome, one in every three (e.g., Vb-to-DJb) joints on average (13), eventually leads to the prohibition of further rearrangement via a signal conveyed from the immature receptor (the so-called pre-TCR) built from the newly synthesized TCRb polypeptide (14)(15)(16)(17).…”

Chromatin accessibility and epigenetic modifications differ between frequently and infrequently rearranging VH genes

“…It has been shown that DNA demethylation of the kappa locus occurs at a late stage in the process of acquiring accessibility for recombination, and it takes place monoallelically (Mostoslavsky et al, 1998;Goldmit et al, 2005). Our data infer that DNA demethylation in V H genes may be limited to the region in the vicinity of the RSS.…”

“…Furthermore, it has been demonstrated that demethylation of L chain genes occurs during B cell development, and is associated with onset of V(D)J recombination (Goodhardt et al, 1993;Mostoslavsky et al, 1998). More recently, several studies have demonstrated that loci active in V(D)J recombination contain nucleosomes with acetylated histone proteins (McMurry and Krangel, 2000;Chowdhury and Sen, 2001;Johnson et al, 2003), and that changes in histone acetylation are dynamic during B cell differentiation.…”