التفاصيل البيبلوغرافية
| العنوان: |
Thymocyte regulatory variant alters transcription factor binding and protects from type 1 diabetes in infants |
| المؤلفون: |
Sandholm, Niina, Garcia, Arcadio Rubio, Pekalski, Marcin L., Inshaw, Jamie R. J., Cutler, Antony J., Todd, John A. |
| المساهمون: |
Research Programs Unit, Medicum, HUS Abdominal Center, University of Helsinki, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine |
| بيانات النشر: |
Nature Publishing Group |
| سنة النشر: |
2022 |
| المجموعة: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| مصطلحات موضوعية: |
CHROMATIN-STATE DISCOVERY, NEGATIVE SELECTION, GENE, ARCHITECTURE, THEMIS, MECHANISMS, RISK, LOCI, 3123 Gynaecology and paediatrics |
| الوصف: |
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. ; Peer reviewed |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| العلاقة: |
The work was funded by the Academy of Finland (299200) and the European Foundation for Study of Diabetes (EFSD) Albert Renold Travel Grant to N.S., and a Strategic Award from the JDRF (4-SRA-2017-473-A-N) and the Wellcome (107212/A/15/Z) to J.A.T. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study makes use of data generated by the Blueprint Consortium. A full list of the investigators who contributed to the generation of the data is available from www.blueprint-epigenome.eu.Funding for the project was provided by the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 282510 BLUEPRINT. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal (www.gtexportal.org).; Sandholm , N , Garcia , A R , Pekalski , M L , Inshaw , J R J , Cutler , A J & Todd , J A 2022 , ' Thymocyte regulatory variant alters transcription factor binding and protects from type 1 diabetes in infants ' , Scientific Reports , vol. 12 , no. 1 , 14137 . https://doi.org/10.1038/s41598-022-18296-4Test; ORCID: /0000-0003-4322-6942/work/119581344; 20253a19-45ed-414a-ae06-b3645dea3ff0; http://hdl.handle.net/10138/348226Test; 000842561700070 |
| الإتاحة: |
http://hdl.handle.net/10138/348226Test |
| حقوق: |
cc_by ; openAccess ; info:eu-repo/semantics/openAccess |
| رقم الانضمام: |
edsbas.49942F5 |
| قاعدة البيانات: |
BASE |
