Journal Article

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

Vardaka, Panagiota, Mumbach, Maxwell R, Imianowski, Charlotte J, Placek, Lindsey, Trynka, Gosia, Fujita, Toshitsugu, Nasrallah, Rabab, Sadiyah, Firas, Unutmaz, Derya, Lozano, Teresa, Liston, Adrian, Cozzani, Adeline, Mitra, Suman, Grant, Francis M, Dogan, Mikail, Lugli, Enrico, Fujii, Hodaka, Whiteside, Sarah K, Andrews, Simon, Kozhaya, Lina, Whyte, Carly E, Kuo, Paula, Glinos, Dafni, Chang, Howard Y, Yang, Jie, Bossini-Castillo, Lara, Roychoudhuri, Rahul

2020

Overview

Genetic variations underlying susceptibility to complex autoimmune and allergic diseases are concentrated within noncoding regulatory elements termed enhancers . 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 contains a distal enhancer that is functional in CD4 regulatory T (T ) cells and required for T -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 T cells, which are unable to control colitis in a cell-transfer model of the disease. In human T 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.

• Subject: Acetylation / Alleles / Animals / Chromosomes, Human, Pair 11 - genetics / Chromosomes, Mammalian - genetics / Colitis - genetics / Colitis - immunology / Enhancer Elements, Genetic - genetics / Female / Forkhead Transcription Factors - metabolism / Genetic Predisposition to Disease - genetics / Histones - metabolism / Humans / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice / Synteny - genetics / T-Lymphocytes, Regulatory - immunology