Promoters, enhancers, and transcription target RAG1 binding during V(D)J recombination

Abstract

RAG1 binding to TCR gene elements is dictated by transcriptional control elements and by transcription itself; these findings provide direct confirmation of the long-held accessibility model.

Noncoding transcription within the Igh distal V H region at PAIR elements affects the 3D structure of the Igh locus in pro-B cells

“…The second step would be the generation of accessibility at the recombination signal sequences (RSSs), which is likely to be accomplished by transcription through the V, D, or J genes and the RSS, which also endows the gene with H3K4me3 and thus will aid in RAG2 recruitment (30,31). Furthermore, RAG1 binding is dependent upon intact promoters and enhancers as well as on transcription across the RSS (37).…”

Transcription-Dependent Generation of a Specialized Chromatin Structure at the TCRβ Locus

“…Subsequently, this model has been strengthened by findings that link V(D)J recombination to transcriptional control elements, such as AR-associated enhancers and promoters, and to several molecular parameters related to open chromatin (including association with active histone marks, DNA hypomethylation, and nuclease hypersensitivity) (3,5). Robust germline transcription at *Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University, UM2, 13288 Marseille, France; (D)J clusters is an initial activation event at all AR loci that generates a focal zone of RAG1/2 binding, termed the recombination center (6,7). More insight into the accessibility model was provided by recent studies demonstrating that the PHD finger domain of RAG2 binds with high affinity to histone H3 trimethylated at K4 (H3K4me3) and that RAG2 is recruited to H3K4me3 domains genome-wide (6)(7)(8).…”

“…Robust germline transcription at *Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University, UM2, 13288 Marseille, France; (D)J clusters is an initial activation event at all AR loci that generates a focal zone of RAG1/2 binding, termed the recombination center (6,7). More insight into the accessibility model was provided by recent studies demonstrating that the PHD finger domain of RAG2 binds with high affinity to histone H3 trimethylated at K4 (H3K4me3) and that RAG2 is recruited to H3K4me3 domains genome-wide (6)(7)(8).…”

Breakpoint sites disclose the role of the V(D)J recombination machinery in the formation of T-cell receptor (TCR) and non-TCR associated aberrations in T-cell acute lymphoblastic leukemia

“…It is well known that chromatin organization influences the ability of RAG to gain access to an authentic RSS. 75 Therefore, access to a cRSS is also decisive for the occurrence of RAG-cRSS mistargeted DSB induction at oncogene loci sites. Reactivity of the RAG protein complex is not only dependent on the recognition of a cRSS by RAG1, but it is likewise dependent on the ability of RAG2 to bind to a H3K4me3-modified nucleosome adjacent to that cRSS in order to enable cleavage at that cRSS site.…”