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Proceedings of the National Academy of Sciences of the United States of America
04 09, 2019;116 (15): 7581-7590.

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
  1. Peng Gao: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
  2. Yasin Uzun: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
  3. Bing He: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
  4. Sarah E Salamati: Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
  5. Julie K M Coffey: Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
  6. Eva Tsalikian: Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
  7. Kai Tan: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104; tank1@email.chop.edu.
PMID: 30910956 DOI: 10.1073/pnas.1815336116

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 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.

Keywords

GWAS diabetes enhancer epigenomics noncoding variant

References

  1. BMC Syst Biol. 2012 Nov 22;6:145 [PMID: 23173819]
  2. Nat Genet. 2015 Mar;47(3):291-5 [PMID: 25642630]
  3. Nat Genet. 2015 Apr;47(4):381-6 [PMID: 25751624]
  4. Nucleic Acids Res. 2015 Jan;43(Database issue):D1117-23 [PMID: 25270877]
  5. Bioinformatics. 2010 Jul 1;26(13):1579-86 [PMID: 20453004]
  6. Cold Spring Harb Protoc. 2009 Oct;2009(10):pdb.ip71 [PMID: 20147036]
  7. Nat Immunol. 2012 Oct;13(10):972-80 [PMID: 22961053]
  8. Mol Immunol. 2017 Oct;90:33-41 [PMID: 28668455]
  9. J Immunol. 2010 Jul 15;185(2):842-55 [PMID: 20548029]
  10. J Pediatr Surg. 2001 Aug;36(8):1150-6 [PMID: 11479845]
  11. Immunity. 2009 Aug 21;31(2):197-208 [PMID: 19682930]
  12. Cell Metab. 2015 Sep 1;22(3):485-98 [PMID: 26299452]
  13. J Autoimmun. 2014 Dec;55:51-62 [PMID: 24934597]
  14. J Immunol. 2012 May 1;188(9):4644-53 [PMID: 22461703]
  15. Cancer Immunol Res. 2014 Nov;2(11):1080-9 [PMID: 25080445]
  16. Immunity. 2008 Jun;28(6):725-7 [PMID: 18549792]
  17. Nat Genet. 2009 Jun;41(6):703-7 [PMID: 19430480]
  18. Biotechniques. 2003 May;34(5):1068-72 [PMID: 12765033]
  19. Cell. 2017 Dec 14;171(7):1573-1588.e28 [PMID: 29224777]
  20. Mol Genet Metab. 2004 Jul;82(3):255-9 [PMID: 15234341]
  21. Eur J Clin Nutr. 2002 Jan;56(1):44-50 [PMID: 11840179]
  22. Diabetes. 2009 Jan;58(1):146-55 [PMID: 18984738]
  23. Genes Immun. 2013 Jan;14(1):62-6 [PMID: 23151489]
  24. Diabetes. 2005 May;54(5):1407-14 [PMID: 15855327]
  25. Nat Rev Immunol. 2016 Feb;16(2):90-101 [PMID: 26688349]
  26. Biochem Biophys Res Commun. 2004 Oct 15;323(2):388-94 [PMID: 15369764]
  27. Nucleic Acids Res. 2007 Jan;35(Database issue):D742-6 [PMID: 17169983]
  28. Blood. 2012 May 10;119(19):4441-50 [PMID: 22310911]
  29. Elife. 2015 Oct 28;4:e07571 [PMID: 26510014]
  30. BMC Immunol. 2008 Apr 16;9:16 [PMID: 18416830]
  31. Proc Natl Acad Sci U S A. 2014 May 27;111(21):E2191-9 [PMID: 24821768]
  32. Immunity. 2011 Mar 25;34(3):435-47 [PMID: 21419664]
  33. Diabetes. 2011 Mar;60(3):1041-4 [PMID: 21270240]
  34. Nihon Rinsho Meneki Gakkai Kaishi. 2012;35(6):503-10 [PMID: 23291485]
  35. J Exp Med. 2017 Jul 3;214(7):1861-1876 [PMID: 28630089]
  36. Blood. 2011 Feb 3;117(5):1734-44 [PMID: 21119112]
  37. Forensic Sci Int Genet. 2015 May;16:17-25 [PMID: 25485478]
  38. Immunol Rev. 2013 Nov;256(1):107-17 [PMID: 24117816]
  39. Biochem Biophys Res Commun. 2007 Oct 12;362(1):44-50 [PMID: 17706604]
  40. Cell. 2014 Sep 11;158(6):1431-1443 [PMID: 25215497]
  41. Science. 2016 Mar 25;351(6280):1454-1458 [PMID: 26940867]
  42. J Diabetes Res. 2016;2016:2532108 [PMID: 28018921]
  43. Cell. 2013 May 23;153(5):1036-49 [PMID: 23706741]
  44. Proc Natl Acad Sci U S A. 2014 Aug 19;111(33):E3432-40 [PMID: 25099355]
  45. Cell. 2016 Nov 17;167(5):1369-1384.e19 [PMID: 27863249]
  46. Diabetes. 2017 Jul;66(7):2033-2043 [PMID: 28607106]
  47. Trends Immunol. 2015 Feb;36(2):81-91 [PMID: 25592731]
  48. Immunity. 2015 Mar 17;42(3):499-511 [PMID: 25769610]
  49. PLoS One. 2010 Sep 28;5(9): [PMID: 20927193]
  50. Nat Genet. 2015 Nov;47(11):1228-35 [PMID: 26414678]
  51. PLoS One. 2009 Jun 22;4(6):e5981 [PMID: 19543397]
  52. Blood. 2013 Apr 4;121(14):2647-58 [PMID: 23355538]
  53. Eur J Immunol. 2013 Nov;43(11):2797-809 [PMID: 24258910]
  54. Nucleic Acids Res. 2017 Jan 4;45(D1):D896-D901 [PMID: 27899670]
  55. Nature. 2015 Oct 1;526(7571):68-74 [PMID: 26432245]
  56. Nucleic Acids Res. 2011 Jan;39(Database issue):D997-1001 [PMID: 20937630]
  57. Nature. 2015 Feb 19;518(7539):337-43 [PMID: 25363779]
  58. Nucleic Acids Res. 2005 Jan 1;33(Database issue):D544-9 [PMID: 15608258]
  59. Diabetes. 2002 Jul;51(7):2264-9 [PMID: 12086959]
  60. Proc Natl Acad Sci U S A. 2016 Jul 5;113(27):E3911-20 [PMID: 27335461]
  61. BMC Immunol. 2012 Mar 14;13:12 [PMID: 22413885]
  62. Genes (Basel). 2013 Sep 16;4(3):499-521 [PMID: 24705215]
  63. Mol Immunol. 2009 Nov;47(1):79-86 [PMID: 19211146]
  64. Nature. 2014 Jul 24;511(7510):428-34 [PMID: 25043047]
  65. Metabolism. 1996 Feb;45(2):248-53 [PMID: 8596498]
  66. Nature. 2014 Mar 20;507(7492):371-5 [PMID: 24646999]
  67. Immunity. 2004 Jan;20(1):37-46 [PMID: 14738763]
  68. J Immunol. 2003 May 15;170(10):4886-90 [PMID: 12734330]
  69. J Biol Chem. 2010 Jan 22;285(4):2545-53 [PMID: 19923223]
  70. J Clin Invest. 2006 May;116(5):1327-36 [PMID: 16628252]
  71. Science. 1995 May 26;268(5214):1185-8 [PMID: 7761837]
  72. Nat Protoc. 2013 Nov;8(11):2281-2308 [PMID: 24157548]
  73. Nat Med. 2013 Mar;19(3):322-8 [PMID: 23396208]
  74. Immunol Cell Biol. 2013 May;91(5):368-76 [PMID: 23567898]
  75. Mol Cell Biol. 2013 Oct;33(20):4106-15 [PMID: 23979593]
  76. Diabetes Metab J. 2012 Jun;36(3):167-80 [PMID: 22737656]
  77. Nat Commun. 2016 Nov 30;7:13683 [PMID: 27901044]
  78. J Clin Invest. 1998 Oct 1;102(7):1369-76 [PMID: 9769329]
  79. Mol Ther. 2008 Jan;16(1):194-202 [PMID: 17984976]

Grants

  1. R01 AA024486/NIAAA NIH HHS
  2. R01 GM104369/NIGMS NIH HHS
  3. R01 GM108716/NIGMS NIH HHS
  4. R01 HG006130/NHGRI NIH HHS

MeSH Term

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

Chemicals

RARA protein, human
Retinoic Acid Receptor alpha
YY1 Transcription Factor
YY1 protein, human
Clinical Trial Journal Article Research Support, N.I.H., Extramural

Links to CNCB-NGDC Resources

GEN: GEND000018 (Novel risk variants affecting enhancers of TH1 and TREG cells in type 1 diabetes [RNA-seq])

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