The role of CTCF in regulating V(D)J recombination

V(D)J recombination in B and T cells is required for the generation of receptors with a broad spectrum of specificity to foreign antigen. A total number of three immunoglobulin (Ig) and four T cell receptor (Tcr) loci can be targeted by the recombinase enzyme (RAG1/2) in a defined series of recombination events, which drive the progression of B and T cell development. This process is regulated at multiple levels to ensure lineage specific, ordered rearrangement and allelic exclusion [ 1]. One key component of this is modulation of chromatin looping and locus contraction, which is important in bringing widely separated gene segments into close contact with each other to enable synapse formation for lineage and stage specific V gene rearrangement [ 2, 3, 4
• , 5 and 6
• ]. Recent studies provide new insight into looping and its role in these processes. In this review we focus on the contribution of the 11 zinc finger nuclear protein, CTCF, in mediating loop formation and conformational changes that are important for the regulation of Ig and Tcr rearrangement.

CTCF plays key roles in the regulation of locus conformation and chromatin looping which is essential for normal V(D)J recombination of antigen-receptor loci. First it acts as an insulator by creating domain barriers separating active and inactive domains: CTCF forms a barrier between the active DH–JH region and the repressed VH segments to avoid premature VH–JH recombination during DH–JHIgh recombination in pre–pro-B cells. Second, CTCF allows enhancer–promoter communication by creating specific hubs: it promotes loop formation between the Eα enhancer and TEA promoter during Tcra recombination in DP T cells. Finally, CTCF creates loops of open/active chromatin domains on antigen receptor loci, which enables synapse formation between widely separated V and (D)J segments during V to (D)J recombination.Figure optionsDownload high-quality image (154 K)Download as PowerPoint slideHighlights
► Conserved CTCF sites within the Igh locus act as insulators.
► PAIR elements link CTCF with Pax5 and Igh locus contraction.
► CTCF sites regulate ordered, lineage specific rearrangement of Igh.
► CTCF regulates proximal versus distal V gene rearrangement at the Igk locus.
► Cohesin regulates Tcra locus conformation and V(D)J rearrangement.