Risk variants disrupting enhancers of T1 and T cells in type 1 diabetes.
Peng Gao, Yasin Uzun, Bing He, Sarah E Salamati, Julie K M Coffey, Eva Tsalikian, Kai Tan
Author Information
- Peng Gao: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
- Yasin Uzun: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
- Bing He: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
- Sarah E Salamati: Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
- Julie K M Coffey: Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
- Eva Tsalikian: Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
- Kai Tan: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104; tank1@email.chop.edu.
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 T1 and T 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.
Child, Preschool
Diabetes Mellitus, Type 1
Enhancer Elements, Genetic
Epigenomics
Female
Genome-Wide Association Study
Humans
Infant
Jurkat Cells
Male
Polymorphism, Single Nucleotide
Retinoic Acid Receptor alpha
Risk Factors
T-Lymphocytes, Regulatory
Th1 Cells
YY1 Transcription Factor
RARA protein, human
Retinoic Acid Receptor alpha
YY1 Transcription Factor
YY1 protein, human
