A distal enhancer at risk locus 11q13.5 promotes suppression of colitis by T_reg cells.

ABSTRACT: Genetic variations underlying susceptibility to complex autoimmune and allergic diseases are concentrated within noncoding regulatory elements termed enhancers¹. The functions of a large majority of disease-associated enhancers are unknown, in part owing to their distance from the genes they regulate, a lack of understanding of the cell types in which they operate, and our inability to recapitulate the biology of immune diseases in vitro. Here, using shared synteny to guide loss-of-function analysis of homologues of human enhancers in mice, we show that the prominent autoimmune and allergic disease risk locus at chromosome 11q13.5^2-7 contains a distal enhancer that is functional in CD4⁺ regulatory T (T_reg) cells and required for T_reg-mediated suppression of colitis. The enhancer recruits the transcription factors STAT5 and NF-?B to mediate signal-driven expression of Lrrc32, which encodes the protein glycoprotein A repetitions predominant (GARP). Whereas disruption of the Lrrc32 gene results in early lethality, mice lacking the enhancer are viable but lack GARP expression in Foxp3⁺ T_reg cells, which are unable to control colitis in a cell-transfer model of the disease. In human T_reg cells, the enhancer forms conformational interactions with the promoter of LRRC32 and enhancer risk variants are associated with reduced histone acetylation and GARP expression. Finally, functional fine-mapping of 11q13.5 using CRISPR-activation (CRISPRa) identifies a CRISPRa-responsive element in the vicinity of risk variant rs11236797 capable of driving GARP expression. These findings provide a mechanistic basis for association of the 11q13.5 risk locus with immune-mediated diseases and identify GARP as a potential target in their therapy.

SUBMITTER: Nasrallah R 

PROVIDER: S-EPMC7116706 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature