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.
A super enhancer controls expression and chromatin architecture within the MHC class II locus
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Parimal Majumder, Joshua T. Lee, Andrew R. Rahmberg, Gaurav Kumar, Tian Mi, Christopher D. Scharer, Jeremy M. Boss; A super enhancer controls expression and chromatin architecture within the MHC class II locus. J Exp Med 3 February 2020; 217 (2): e20190668. doi: https://doi.org/10.1084/jem.20190668
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