4.7 Article

Thymocyte regulatory variant alters transcription factor binding and protects from type 1 diabetes in infants

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SCIENTIFIC REPORTS
卷 12, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41598-022-18296-4

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资金

  1. Academy of Finland [299200]
  2. European Foundation for Study of Diabetes (EFSD) Albert Renold Travel Grant
  3. JDRF [4-SRA-2017-473-A-N]
  4. Wellcome [107212/A/15/Z]
  5. European Union's Seventh Framework Programme (FP7/2007-2013) [282510 BLUEPRINT]
  6. Common Fund of the Office of the Director of the National Institutes of Health
  7. NCI
  8. NHGRI
  9. NHLBI
  10. NIDA
  11. NIMH
  12. NINDS

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A genetic susceptibility locus on chromosome 6q22.33 for type 1 diabetes (T1D) was identified, and the rs138300818 variant was found to play a role in promoting the development of early-onset T1D. Thymocyte genomic data revealed DNA sequence motifs underlying histone modifications and variants disrupting transcription factor binding motifs. The study suggests that thymic THEMIS gene expression and the rs138300818 variant contribute to the development of T1D.
We recently mapped a genetic susceptibility locus on chromosome 6q22.33 for type 1 diabetes (T1D) diagnosed below the age of 7 years between the PTPRK and thymocyte-selection-associated (THEMIS) genes. As the thymus plays a central role in shaping the T cell repertoire, we aimed to identify the most likely causal genetic factors behind this association using thymocyte genomic data. In four thymocyte populations, we identified 253 DNA sequence motifs underlying histone modifications. The G insertion allele of rs138300818, associated with protection from diabetes, created thymocyte motifs for multiple histone modifications and thymocyte types. In a parallel approach to identifying variants that alter transcription factor binding motifs, the same variant disrupted a predicted motif for Rfx7, which is abundantly expressed in the thymus. Chromatin state and RNA sequencing data suggested strong transcription overlapping rs138300818 in fetal thymus, while expression quantitative trait locus and chromatin conformation data associate the insertion with lower THEMIS expression. Extending the analysis to other T1D loci further highlighted rs66733041 affecting the GATA3 transcription factor binding in the AFF3 locus. Taken together, our results support a role for thymic THEMIS gene expression and the rs138300818 variant in promoting the development of early-onset T1D.

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