A Role for Histone Acetylation in the Developmental Regulation of V(D)J Recombination

Abstract

VDJ recombination is developmentally regulated in vivo by enhancer-dependent changes in the accessibility of chromosomal recombination signal sequences to the recombinase, but the molecular nature of these changes is unknown. Here histone H3 acetylation was measured along versions of a transgenic VDJ recombination reporter and the endogenous T cell receptor alpha/delta locus. Enhancer activity was shown to impart long-range, developmentally regulated changes in H3 acetylation, and H3 acetylation status was tightly linked to VDJ recombination. H3 hyperacetylation is proposed as a molecular mechanism coupling enhancer activity to accessibility for VDJ recombination.

TEA regulates local TCR‐Jα accessibility through histone acetylation

“…2a), the transition to the DP stage was remarkably accompanied with a shift to a hyperacetylated state (Fig. 2b), as first noticed by McMurry and Krangel on TEA, J § 25 and C § [12]. We extended the study to histone H4 and the same global increase in the acetylation level was observed ( Fig.…”

“…For H4, the overall levels of acetylation were weaker than for H3 and no remarkable gradient could be revealed. In their pioneer study, McMurry and Krangel [12] showed that histone H3 is acetylated along the TCR § locus prior to the V § J § rearrangements (they used the RAG2-/-×tgTCR g model, similar to the RT3 model), However, the authors restricted their study to histone H3 and to one J § segment only (J § 25). Here we show that the acetylation of histone H4 is as remarkable as the acetylation of histone H3; furthermore the study of several J § segments along the J § cluster allows us to reveal a gradient of acetylation for H3, that mirrors the gradient of usage of the J § segments, with a maximum at the 5´end of the cluster where the first waves of rearrangements occur.…”

“…We wish to put these data back in perspective of the particular features of the TCR § rearrangements: the V § J § rearrangements progress from 5' to 3' in the J § cluster, on both alleles, the most 5´J § segments being predominantly used [21][22][23][24]; Enh § controls the global accessibility of the TCR § through the global control of histone H3 acetylation [12]. Such a global accessibility does not account for the gradual usage of the J § segments.…”

“…All the in vitro results obtained so far seem to confirm that a nucleosomal RSS is refractory to binding and cleavage by the RAG proteins [9][10][11]; the studies, however, diverge with regards to the possibility to overcome the block by acetylating the tails of the histones. In vivo, rearrangements in the endogenous TCR § /ˇor in a TCRˇminilocus correlate with an enhancer-dependent acetylation of the DNA in the region [12] and the block of V(D)J recombination in an enhancer-deficient mouse model (Enh g TCR) can be partially overcome by histone deacetylases inhibitor drugs [13].…”

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

“…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. Furthermore, acetylation of histones is not uniform throughout the V H locus, but is narrowly confined to promoters, coding regions and RSSs, with lower levels of histone acetylation in intergenic regions (Johnson et al, 2003;Espinoza and Feeney, 2005).…”