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Review
. 2012 Apr;33(4):153-9.
doi: 10.1016/j.it.2012.02.004. Epub 2012 Mar 20.

Cohesin, CTCF and lymphocyte antigen receptor locus rearrangement

Vlad C Seitan  1 , Michael S Krangel, Matthias Merkenschlager
Affiliations
Review

Cohesin, CTCF and lymphocyte antigen receptor locus rearrangement

Vlad C Seitan et al. Trends Immunol. 2012 Apr.

Abstract

The somatic recombination of lymphocyte antigen receptor loci is integral to lymphocyte differentiation and adaptive immunity. Here we review the relation of this highly choreographed process with the zinc finger protein CTCF and with cohesin, a protein complex best known for its essential functions in post-replicative DNA repair and chromosome segregation during the cell cycle. At lymphocyte antigen receptor loci, CTCF and cohesin shape long-range interactions and contribute to V(D)J recombination by facilitating lineage- and developmental-stage-specific transcription and accessibility.

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Conflict of interest statement

The authors have no financial conflict of interest.

Figures

Figure 1
Figure 1. Developmentally regulated positioning and compaction of the Ig heavy chain locus
a) The position of loci within the nucleus often correlates with their expression: transcriptionally active regions of the genome are often located towards the centre of the nucleus [30]. Igh loci are positioned at the periphery of the nucleus in multi-lineage progenitors and remain there in T cell progenitors. Prior to their rearrangement in B cell progenitors, however, Igh loci are re-positioned towards the center of the nucleus (based on [3]). b) A two-stage model of the developmental regulation of Igh locus conformation where the folding of individual domains (step 1) occurs prior to onset of rearrangement to be followed by the approximation of the domains (step 2) at the onset of rearrangement [4, 5].
Figure 2
Figure 2. Composition and function of the cohesin complex
a) The composition of the cohesin complex. b) The cohesin complex holds sister chromatids together from the time of DNA replication in S-phase until mitosis and forms long-range interactions between its binding sites in interphase. These binding sites are defined by the positioning of cohesin loading factors at active promoters and enhancers [–9], by the mammalian insulator protein CTCF [10, 11], or both [8].
Figure 3
Figure 3. A new class of regulatory elements within the distal V gene regions of the Ig heavy chain locus
PAIR elements bind E2A, CTCF and cohesin throughout B cell development, recruit Pax-5 specifically in pro-B cells, and mediate developmentally regulated antisense transcription [25].
Figure 4
Figure 4. Loss of CTCF affects long-range interactions and rearrangement at the Igκ light chain locus [16]
The intronic iEκ enhancer was taken as the viewpoint for 3C-seq analysis of long-range interactions across the Igκ locus. In control cells (black lines), the iEκ enhancer interacted more or less equally with multiple Vκ genes across the Igκ locus. Interactions of iEκ were restricted to the Igκ locus. In CTCF-deficient cells, by contrast, the iEκ enhancer interacted preferentially with enhancer-proximal Vκ genes, while enhancer-distal Vκ genes were neglected (the thickness of the lines indicates the relative strength of each interaction). Interactions of iEκ were no longer restricted to the Igk locus. This pattern of long-range interactions was reflected in the pattern of transcription across the Igk locus and in the range of Vκ gene rearrangements, which were severely restricted in CTCF deficient cells.
Figure 5
Figure 5
Cohesin facilitates enhancer-promoter interactions, transcription, and rearrangement of the Tcra locus. The Eα enhancer and TEA promoter are 80 kb apart in the linear sequence of DNA (left). Cohesin-facilitated contacts between these regulatory elements (right) promote germline transcription, histone modification, recruitment of the recombination machinery and, ultimately, somatic recombination of Tcra [17].
Figure 6
Figure 6. CTCF and cohesin demarcate functional boundaries in and around lymphocyte receptor gene loci
a) CTCF binding sites limit antisense transcription, accessibility, long-range interactions and premature rearrangement of Igh [18]. b) CTCF and cohesin cooperate to form a boundary at Tcra. A CTCF- and cohesin-binding site with known insulator function is located between Tcra and the neighbouring house keeping gene Dad1. Cohesin deletion results in increased transcription of Dad1, suggesting that cohesin is required for the formation of a boundary that limits Eα enhancer activity to the Tcra locus [17].
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