Histone methylation and V(D)J recombination

Abstract

V(D)J recombination is the process by which the diversity of antigen receptor genes is generated and is also indispensable for lymphocyte development. This recombination event occurs in a cell lineage-and stagespecific manner, and is carefully controlled by chromatin structure and ordered histone modifications. The recombinationally active V(D)J loci are associated with hypermethylation at lysine4 of histone H3 and hyperacetylation of histones H3/H4. The recombination activating gene 1 (RAG1) and RAG2 complex initiates recombination by introducing double-strand DNA breaks at recombination signal sequences (RSS) adjacent to each coding sequence. To be recognized by the RAG complex, RSS sites must be within an open chromatin context. In addition, the RAG complex specifically recognizes hypermethylated H3K4 through its plant homeodomain (PHD) finger in the RAG2 C terminus, which stimulates RAG catalytic activity via that interaction. In this review, we describe how histone methylation controls V(D)J recombination and discuss its potential role in lymphoid malignancy by mistargeting the RAG complex.

RAG Recombinase as a Selective Pressure for Genome Evolution

“…With this perspective, deregulation of the H3K4me3 levels or changes in the transcriptional program in rag -expressing cells could allow the recombinase to bind to regions that have not been under selective pressure and thus have remained enriched in RSS, potentially leading to genomic instability. This proposition is consistent with evidence that H3K4me3 contribute to illegitimate recombination through RAG-mistargeting to cRSS (Shimazaki and Lieber 2014). …”

PEG3 control on the mammalian MSL complex

“…Reducing the gene dosage of human PEG3 might have been part of cellular responses to trigger MSL to cope with DNA damages that are frequently occurring in cancer cells. Besides DNA repair pathways, many cellular pathways are also known to require open chromatin structure, such as DNA replication and recombination [26–28]. Thus, it is reasonable to predict that the hyperacetylation on H4K16 observed in Peg3-KO samples may be designed for various unknown functional needs for the affected genes.…”

Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development

“…Loss of H3K36me3 did not significantly affect the methylation states of mono-, di-, or tri-methyl lysine-27 or mono-and di-methyl lysine-36 residues in this region ( Figure S5C). We detected equivalent recruitment of Rag1 and Hmgb2 to this same region on the Igh locus (Shimazaki and Lieber, 2014;Johnson et al, 2010;Ji et al, 2010;Matheson and Corcoran, 2012) ( Figure 4D), suggesting that the initiation phase of the V(D)J recombination reaction was intact. We were also not able to detect in sorted FrA proB cells any evidence of Rag1 recruitment or H3K36me3 at variable gene families on the Igh locus in either Setd2-deficient cells or controls ( Figure S5D).…”

“…As accessibility of this region is critical for B cell development (Chowdhury and Sen, 2001;Chakraborty et al, 2009), we wanted to ascertain if the loss of H3K36me3 affected local chromatin architecture or accessibility. In proB cells, ablation of H3K36me3 neither affected chromatin accessibility ( Figures 4B and S5B) nor disrupted the local levels of H3K4me3 and H3K9ac ( Figure 4C), two histone modifications essential for maintaining an open and actively transcribed chromatin structure at this regulatory region (Chowdhury and Sen, 2001;Chakraborty et al, 2009) and for H3K4me3, the recruitment and activation of the Rag2 protein itself (Shimazaki and Lieber, 2014;Johnson et al, 2010;Ji et al, 2010;Matheson and Corcoran, 2012;Bettridge et al, 2017). Loss of H3K36me3 did not significantly affect the methylation states of mono-, di-, or tri-methyl lysine-27 or mono-and di-methyl lysine-36 residues in this region ( Figure S5C).…”