Risk variants disrupting enhancers of T<sub>H</sub>1 and T<sub>REG</sub> cells in type 1 diabetes.
other · Level V
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- Record sourced from PubMed, PMID 30910956.
- Also identified by DOI 10.1073/pnas.1815336116 and PMC identifier 6462079.
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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 T<sub>H</sub>1 and T<sub>REG</sub> 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.
Medical subject headings
- Diabetes Mellitus, Type 1
- Enhancer Elements, Genetic
- Polymorphism, Single Nucleotide
- Retinoic Acid Receptor alpha
- T-Lymphocytes, Regulatory
- Th1 Cells
- YY1 Transcription Factor