A super enhancer controls expression and chromatin architecture within the MHC class II locus

Abstract

Super enhancers (SEs) play critical roles in cell type–specific gene regulation. The mechanisms by which such elements work are largely unknown. Two SEs termed DR/DQ-SE and XL9-SE are situated within the human MHC class II locus between the HLA-DRB1 and HLA-DQA1 genes and are highly enriched for disease-causing SNPs. To test the function of these elements, we used CRISPR/Cas9 to generate a series of mutants that deleted the SE. Deletion of DR/DQ-SE resulted in reduced expression of HLA-DRB1 and HLA-DQA1 genes. The SEs were found to interact with each other and the promoters of HLA-DRB1 and HLA-DQA1. DR/DQ-SE also interacted with neighboring CTCF binding sites. Importantly, deletion of DR/DQ-SE reduced the local chromatin interactions, implying that it functions as the organizer for the local three-dimensional architecture. These data provide direct mechanisms by which an MHC-II SE contributes to expression of the locus and suggest how variation in these SEs may contribute to human disease and altered immunity.

The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins

“…Recently, the region between the HLA-DRB1 and HLA-DQA1 loci in the MHC-II region was shown to display characteristics of a super-enhancer (SE) region [ 65 , 66 ]. Two SEs were identified in this region and termed DR/DQ-SE and XL9-SE, and were shown to be highly enriched in disease-associated SNPs.…”

“…CRISPR/Cas9-mediated deletion of the DR/DQ-SE led to a reduction of HLA-DRB1 and HLA-DQA1 expression. Local chromatin interactions were disrupted by SE-deletions, suggesting that the SEs are involved in the organization of the local three-dimensional chromatin architecture [ 66 ].…”

Roadmap to a plasma cell: Epigenetic and transcriptional cues that guide B cell differentiation

“…104,105 In B cells, a SEs termed DR/DQ-SE resides between the HLA-DRB1 and HLA-DQA1 genes in the human MHC-II locus and is the densest region in the genome for non-coding disease-associated SNPs. 106 The DR/DQ-SE binds CIITA,…”

“…SEs are highly enriched for disease‐associated SNPs compared with conventional enhancers 104,105 . In B cells, a SEs termed DR/DQ‐SE resides between the HLA‐DRB1 and HLA‐DQA1 genes in the human MHC‐II locus and is the densest region in the genome for non‐coding disease‐associated SNPs 106 . The DR/DQ‐SE binds CIITA, 107,108 the essential co‐activator for all MHC‐II genes, and is flanked by a CTCF‐bound insulator element that helps to establish the local 3D architecture and MHC‐II gene expression 101,109 .…”

“…In B cells from subjects with systemic lupus erythematosus (SLE), thereis evidence that sequence variation within the DR/DQ-SE is developmentally important and impacts the 3D architecture and transcription factor binding 110,111. Functionally, the deletion of the DR/DQ-SE impacted the ability of B cells to activate CD4 T cells 106. This finding highlights the potential for how polymorphisms in enhancers can generate variation in MCH-II expression with the potential to regulate B cell:T cell interactions and the outcome of TD immune responses.Given the long-established associations of MHC-II-coding variationwith disease, additional work is needed to determine the precise transcription factor-binding sites that are impacted and the exact developmental stages and cell types in which different SNPs affect MHC-II expression.…”