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Review
. 2020 Feb;11(1):37-51.
doi: 10.1080/21541264.2019.1699383. Epub 2019 Dec 12.

Enhancers as regulators of antigen receptor loci three-dimensional chromatin structure

E Mauricio Barajas-Mora  1   2 , Ann J Feeney  1
Affiliations
Review

Enhancers as regulators of antigen receptor loci three-dimensional chromatin structure

E Mauricio Barajas-Mora et al. Transcription. 2020 Feb.

Abstract

Enhancers are defined as regulatory elements that control transcription in a cell-type and developmental stage-specific manner. They achieve this by physically interacting with their cognate gene promoters. Significantly, these interactions can occur through long genomic distances since enhancers may not be near their cognate promoters. The optimal coordination of enhancer-regulated transcription is essential for the function and identity of the cell. Although great efforts to fully understand the principles of this type of regulation are ongoing, other potential functions of the long-range chromatin interactions (LRCIs) involving enhancers are largely unexplored. We recently uncovered a new role for enhancer elements in determining the three-dimensional (3D) structure of the immunoglobulin kappa (Igκ) light chain receptor locus suggesting a structural function for these DNA elements. This enhancer-mediated locus configuration shapes the resulting Igκ repertoire. We also propose a role for enhancers as critical components of sub-topologically associating domain (subTAD) formation and nuclear spatial localization.

Keywords: 3D structure; Enhancer; Igκ; V(D)J recombination; antibody repertoire; antigen receptor loci; chromatin conformation capture; long-range chromatin interactions; loop extrusion; nuclear topology; subTAD.

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Figures

Figure 1.
Figure 1.
V(D)J recombination during B cell development and subTAD organization in the Igκ locus. (a) Early stages of B cell development. IgH rearrangement takes place in pro-B cells, and light chain (Igκ or Igλ) rearrangement predominantly takes place in pre-B cells, although a low amount of Igκ rearrangement takes place in pro-B cells. (b) Location of subTADs in IL7-cultured pro-B cells. The iEκ, E88, E135, and E137 enhancers are indicated. CTCF binding sites at subTAD boundaries are represented by vertical black bars, and their orientation is indicated by the arrows. SubTADs are represented as red triangles. Predominant subTADs (sT) are labeled 1 to 5. (c) Relative Vκ rearrangement in E88-deleted vs WT pre-B cells is shown as a heat map. Intensity of green indicates higher and red indicates lower rearrangement of the E88-deleted cells compared to WT.
Figure 2.
Figure 2.
LRCIs correlate with H3K4me1 binding at pro-B and pre-B cells. UCSC Genome Browser presentation of datasets for 4C LRCIs from E88 viewpoint (track 1), iEκ viewpoint (track 2), and ChIP-seq for H3K4me1 in pro-B cells (track 3). Datasets set for 4C LRCIs from E88 viewpoint (track 4), iEκ viewpoint (track 5), and ChIP-seq for H3K4me1 in pre-B cells (track 6). 4C data is shown as reads per million (RPM) in 10 kb windows. Blue highlights show examples of the correlation between H3K4me1 binding and 4C LRCIs. The anchor represents the location of the viewpoint and the red highlight shows the area where the reads were removed for the analysis of each viewpoint.
Figure 3.
Figure 3.
Changes in LRCIs patterns and possible subTAD boundary disruption caused by E88 deletion. (a) LRCIs in WT pro-B cells as determined by 4C with the anchor in the E88 area. (b) LRCIs in E88Δ pro-B cells from the E88 area. Downstream from E88, the subTAD boundary is not able to restrict the LRCIs coming from the E88 area in E88Δ cells. LRCIs are indicated by black lines. E88 and the iEκ enhancer are shown. CTCFs in subTAD boundaries are represented by vertical bars. CTCF binding site orientation is shown by the arrows.
Figure 4.
Figure 4.
Potential enhancer elements in the V-gene region of the TCR loci. Genome browser view for the enhancer marks H3K4me1 (GSM1000102) and H3K7Ac (GSM1000103) in thymus [133]. (A) TCR α/δ locus. (B) TCR Ɣ locus. (C) TCR β locus. V and J genes are indicated at the bottom of each track.*TRDV5 is located within this J region. Potential enhancer elements in the V gene region are highlighted in blue.
Figure 5.
Figure 5.
Model for Igκ locus structure and changes caused by E88 deletion. (a) During the pro-B cell stage, the Igκ locus is in a compacted conformation. The regulatory region, where the iEκ, 3ʹExκ, Ed enhancers and the J genes are located, is in close contact with the subTADs that contain the E88 and E135/137 enhancers. (b) E88 deletion impairs the ability of the E88-containing subTAD to come in close proximity to the recombination center and the E135/137-containing subTAD. (c) In WT cells upon differentiation into pre-B cells, new recruitment of CTCF and cohesin, especially in the proximal part of the locus presumably results in changes in the subTAD landscape. Here, all subTADs have similar chances to get in close proximity to the recombination center to allow the proper V(D)J recombination of all Vκ genes. (D) As a consequence of E88 deletion, subTADs in the middle part of the locus have a reduced likelihood to interact with the recombination center. This causes a reduction of rearrangement frequency of V genes in the E88-containing subTAD as well as the downstream adjacent subTAD, and an increase of relative rearrangement of the more distant subTADs.
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