Risk variants disrupting enhancers of T H 1 and T REG cells in type 1 diabetes

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

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Child, Preschool
  • Diabetes Mellitus, Type 1* / genetics
  • Diabetes Mellitus, Type 1* / immunology
  • Diabetes Mellitus, Type 1* / pathology
  • Enhancer Elements, Genetic*
  • Epigenomics
  • Female
  • Genome-Wide Association Study
  • Humans
  • Infant
  • Jurkat Cells
  • Male
  • Polymorphism, Single Nucleotide*
  • Retinoic Acid Receptor alpha* / genetics
  • Retinoic Acid Receptor alpha* / immunology
  • Risk Factors
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Th1 Cells / immunology*
  • Th1 Cells / pathology
  • YY1 Transcription Factor* / genetics
  • YY1 Transcription Factor* / immunology

Substances

  • RARA protein, human
  • Retinoic Acid Receptor alpha
  • YY1 Transcription Factor
  • YY1 protein, human