TY - JOUR
T1 - Risk variants disrupting enhancers of TH1 and TREG cells in type 1 diabetes
AU - Gao, Peng
AU - Uzun, Yasin
AU - He, Bing
AU - Salamati, Sarah E.
AU - Coffey, Julie K.M.
AU - Tsalikian, Eva
AU - Tan, Kai
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank the Research Information Services at the Children’s Hospital of Philadelphia for providing computing support. This work was supported by National Institutes of Health Grants GM104369, GM108716, HG006130, and AA024486 (to K.T.).
Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.
PY - 2019/4/9
Y1 - 2019/4/9
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.1815336116
DO - 10.1073/pnas.1815336116
M3 - Article
C2 - 30910956
AN - SCOPUS:85064112327
SN - 0027-8424
VL - 116
SP - 7581
EP - 7590
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 15
ER -