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Proc Natl Acad Sci U S A. 2019 Apr 9;116(15):7581-7590. doi: 10.1073/pnas.1815336116. Epub 2019 Mar 25.

Risk variants disrupting enhancers of TH1 and TREG cells in type 1 diabetes.

Gao P1,2,3, Uzun Y1,2,3, He B1,2,3, Salamati SE4, Coffey JKM4, Tsalikian E4, Tan K5,2,3,6,7,8.

Author information

1
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
2
Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
3
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
4
Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
5
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104; tank1@email.chop.edu.
6
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
7
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
8
Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Abstract

Genome-wide association studies (GWASs) have revealed 59 genomic loci associated with type 1 diabetes (T1D). Functional interpretation of the SNPs located in the noncoding region of these loci remains challenging. We perform epigenomic profiling of two enhancer marks, H3K4me1 and H3K27ac, using primary TH1 and TREG cells isolated from healthy and T1D subjects. We uncover a large number of deregulated enhancers and altered transcriptional circuitries in both cell types of T1D patients. We identify four SNPs (rs10772119, rs10772120, rs3176792, rs883868) in linkage disequilibrium (LD) with T1D-associated GWAS lead SNPs that alter enhancer activity and expression of immune genes. Among them, rs10772119 and rs883868 disrupt the binding of retinoic acid receptor α (RARA) and Yin and Yang 1 (YY1), respectively. Loss of binding by YY1 also results in the loss of long-range enhancer-promoter interaction. These findings provide insights into how noncoding variants affect the transcriptomes of two T-cell subtypes that play critical roles in T1D pathogenesis.

KEYWORDS:

GWAS; diabetes; enhancer; epigenomics; noncoding variant

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