@misc{10481/88835,
year = {2020},
url = {https://hdl.handle.net/10481/88835},
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 11q13.52-7 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.},
organization = {The research was supported by Wellcome Trust / Royal Society Fellowship 105663/Z/14/Z, Wellcome Trust grant
WT206194, Biotechnology and Biological Sciences Research Council grants BB/N007794/1, BBS/E/B/000C0427
and BBS/E/B/000C0428, Cancer Research UK grant C52623/A22597, MRC grants MR/N014995/1, MR/
S024468/1 and MC_UU_00014/5, Wellcome Trust Major Award 208363/Z/17/Z, Associazione Italiana per la
Ricerca sul Cancro (AIRC) grant IG 20607, and US National Institutes of Health (NIH) grants RM1-HG007735,
U19-AI142733 and R01-AI121920. We thank members of the Babraham Institute Biological Services Unit, flow
cytometry facility and sequencing facility, and Wellcome Sanger Institute flow cytometry, sequencing, IT and data
access facilities for data generation and processing. We thank all participating blood donors, and Cambridge and
Oxford NHS Blood and Transplant, New York Blood Center and Policlinico San Matteo Pavia Fondazione for the
recruitment of study participants. We thank Federica De Paoli (Humanitas) for processing human PBMC samples
and Martin Turner, Klaus Okkenhaug, Ethan Shevach, Michelle Linterman and Geoff Butcher for support and
discussion.},
title = {A distal enhancer at the 11q13.5 risk locus promotes Treg-mediated suppression of colitis},
doi = {10.1038/s41586-020-2296-7},
author = {Nasrallah, Nasrallah and Bossini Castillo, Lara María},
}