A distal enhancer at risk locus 11q13.5 promotes suppression of colitis by T
Acetylation, Alleles, Animals, Chromosomes, Human, Pair 11, Chromosomes, Mammalian, Colitis, Enhancer Elements, Genetic, Female, Forkhead Transcription Factors, Genetic Predisposition to Disease, Histones, Humans, Membrane Proteins, Mice, Synteny, T-Lymphocytes, Regulatory
Nature 2020 Jul 16; 583(7816):447-452
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 11q13.52-7 contains a distal enhancer that is functional in CD4+ regulatory T (Treg) cells and required for Treg-mediated suppression of colitis. The enhancer recruits the transcription factors STAT5 and NF-κB 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+ Treg cells, which are unable to control colitis in a cell-transfer model of the disease. In human Treg 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.
Nasrallah, Rabab; Imianowski, Charlotte J; Bossini-Castillo, Lara; Grant, Francis M; Dogan, Mikail; Placek, Lindsey; Kozhaya, Lina; Kuo, Paula; Sadiyah, Firas; Whiteside, Sarah K; Mumbach, Maxwell R; Glinos, Dafni; Vardaka, Panagiota; Whyte, Carly E; Lozano, Teresa; Fujita, Toshitsugu; Fujii, Hodaka; Liston, Adrian; Andrews, Simon; Cozzani, Adeline; Yang, Jie; Mitra, Suman; Lugli, Enrico; Chang, Howard Y; Unutmaz, Derya; Trynka, Gosia; and Roychoudhuri, Rahul, "A distal enhancer at risk locus 11q13.5 promotes suppression of colitis by T" (2020). Faculty Research 2020. 172.