Selective control of HLA-DRB1 and HLA-DQA1 transcription through DR/DQ super enhancer microelements.

MHC-II gene expression requires promoter-proximal and distal organizing elements. A super enhancer located between the HLA-DR and -DQ genes was dissected into five microdomains (regions A-E) to define its mechanism of action. Regions A and B were required for maximal expression of HLA-DQA1. Region A facilitated HLA-DQA1 expression and substituted for region B in its absence, as well as mediating longer-range interactions with distal CTCF sites. Region D modulated HLA-DRB1 through specific 3D chromatin interactions, whereas a local insulator element (XL9) broadly interacted with the SE. Through deletion of HLA-DRB1 proximal-promoter elements, HLA-DQ expression increased by co-opting interactions with region D, indicating that competition between microelements regulates the absolute levels of MHC-II genes. Together, these data define an additional layer of control for MHC-II genes encoded in one of the most polymorphic and disease-associated regions of the human genome.