Abstract
At both the immunoglobulin heavy and kappa light chain loci, there are >100 functional variable (V) genes spread over >2 Mb that must move into close proximity in 3D space to the (D)J genes to create a diverse repertoire of antibodies. Similar events take place at the T cell receptor (TCR) loci to create a wide repertoire of TCRs. In this review, we will discuss the role of CTCF in forming rosette-like structures at the antigen receptor (AgR) loci, and the varied roles it plays in alternately facilitating and repressing V(D)J rearrangements. In addition, non-coding RNAs, also known as germline transcription, can shape the 3D configuration of the Igh locus, and presumably that of the other AgR loci. At the Igh locus, this could occur by gathering the regions being transcribed in the VH locus into the same transcription factory where Iμ is being transcribed. Since the Iμ promoter, Eμ, is adjacent to the DJH rearrangement to which one V gene will ultimately rearrange, the process of germline transcription itself, prominent in the distal half of the VH locus, may play an important and direct role in locus compaction. Finally, we will discuss the impact of the transcriptional and epigenetic landscape of the Igh locus on VH gene rearrangement frequencies.
Highlights
Antigen receptor (AgR) loci are facing a uniquely difficult task to produce a great diversity of receptors in order to recognize the limitless possibility of antigens present in the environment of an organism
The results showed that the locus could be divided into three ~1 Mb compartments in pre–pro-B cells in which multiple chromatin loops formed rosette-like structures (Figure 2)
We analyzed the binding pattern of cohesin by performing a chromatin immunoprecipitation (ChIP)/qPCR for Rad21, one of the cohesin subunits. This revealed that the level of Rad21 binding was higher in pro-B cells than in pre-B cells or thymocytes for many sites, suggesting cohesin may have a greater role than CTCF in specifying the developmental stage in which immunoglobulin heavy chains (Igh) recombination occurs [28]
Summary
Antigen receptor (AgR) loci are facing a uniquely difficult task to produce a great diversity of receptors in order to recognize the limitless possibility of antigens present in the environment of an organism. This revealed that the level of Rad21 binding was higher in pro-B cells than in pre-B cells or thymocytes for many sites, suggesting cohesin may have a greater role than CTCF in specifying the developmental stage in which Igh recombination occurs [28].
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