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

Peng Gao, Yasin Uzun, Bing He, Sarah E. Salamati, Julie K.M. Coffey, Eva Tsalikian, Kai Tan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)7581-7590
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number15
DOIs
StatePublished - Apr 9 2019

All Science Journal Classification (ASJC) codes

  • General

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