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

Area of Science:

• Genomics
• Molecular Biology
• Immunology

Background:

• Super enhancers (SEs) are crucial for cell-specific gene regulation, but their precise mechanisms remain unclear.
• SEs within the human MHC class II locus, specifically DR/DQ-SE and XL9-SE, are associated with disease-causing single nucleotide polymorphisms (SNPs).

Purpose of the Study:

• To investigate the functional role of DR/DQ-SE and XL9-SE in the human MHC class II locus.
• To elucidate the mechanisms by which these SEs regulate gene expression and local chromatin architecture.

Main Methods:

• CRISPR/Cas9 gene editing was employed to generate SE deletion mutants.
• Gene expression levels of HLA-DRB1 and HLA-DQA1 were quantified.
• Chromatin interaction analyses were performed to assess 3D genome organization.

Main Results:

• Deletion of DR/DQ-SE led to decreased expression of HLA-DRB1 and HLA-DQA1 genes.
• SEs were observed to interact with each other, gene promoters, and CTCF binding sites.
• Removal of DR/DQ-SE diminished local chromatin interactions, indicating its role in organizing 3D architecture.

Conclusions:

• The study provides direct evidence for the mechanism by which an MHC-II SE influences locus expression.
• Variations within these SEs may contribute to human diseases and altered immune responses.