Epigenetic and 3-dimensional regulation of V(D)J rearrangement of immunoglobulin genes

Abstract

V(D)J recombination is a crucial component of the adaptive immune response, allowing for the production of a diverse antigen receptor repertoire (Ig and TCR). This review will focus on how epigenetic regulation and 3-dimensional (3D) interactions may control V(D)J recombination at Ig loci. The interplay between transcription factors and post-translational modifications at the Igh, Igκ, and Igλ loci will be highlighted. Furthermore, we propose that the spatial organization and epigenetic boundaries of each Ig loci before and during V(D)J recombination may be influenced in part by the CTCF/cohesin complex. Taken together, the many epigenetic and 3D layers of control ensure that Ig loci are only rearranged at appropriate stages of B cell development.

Fig 1

Histone posttranslational modifications on Ig genes. ChIP was performed on RAG^−/− pro-B cells for H3K4me3, acetylated H3, and H3K27me3. H3K4me3 and AcH3 were predominantly on J genes, but not on V or D genes to any large extent [7]. H3K27me3, the histone modification catalyzed by Ezh2, was present on proximal V_H genes but not on distal V_H genes [30]. In the absence of Ezh2, distal V_H genes are unable to undergo V(D)J rearrangement.

Fig. 2

Genomic structure of germline immunoglobulin loci and locations of CTCF sites. Enhancers are depicted by yellow circles, V genes are depicted by blue boxes, and constant regions are represented by red squares. Genomic locations of CTCF sites in RAG^−/− pro-B cells (Igh locus) and μ⁺RAG^−/− pre-B cells (Igκ and Igλ loci) are depicted by black lines below the schematics of each loci [38].

Fig. 3

Proposed model of the role of CTCF in V(D)J recombination. Cartoon of germline genomic structure of the Igh locus with CTCF sites (green boxes) located throughout the V_H locus, 5′ of DFL16.1, and in the 3′RR (top portion of schematic). Loops between CTCF sites located 5′ of DFL16.1 and CTCF sites clustered in the 3′RR may form a loop to exclude the V_H portion of the locus during the stage of D_H-J_H recombination (middle portion of schematic). During V_H to D_H-J_H recombination, CTCF/cohesin may facilitate the compaction of the Igh locus and the formation of a multi-loop structure, giving all V_H genes access to the D_H-J_H gene segment (lower portion of schematic). Grey rings depict cohesin rings. Yellow circles represent enhancers.

Fig. 4

CTCF sites near DFL16.1 may form a boundary to insulate the D_H-C_H-J_H region of the Igh locus from the V_H portion of the locus. Middle portion of schematic highlights region of the Igh locus located between the CTCF sites 5′ of DFL16.1 and CTCF sites in the 3′RR. Lower portion of schematic depicts the targeted insertion of the V_H gene segment (blue box) into the region 5′ of DFL16.1 in studies by Bates et al [43]. The targeted insertion was just 3′ of the two CTCF sites 5′ of DFL16.1. Green boxes depict CTCF sites. Yellow circles represent enhancers.