期刊
HUMAN MOLECULAR GENETICS
卷 21, 期 2, 页码 322-333出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr468
关键词
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资金
- Wellcome Trust [076113/C/04/Z, 076113, 082549/Z/07/Z, 089989/Z/09/Z, 079895]
- Wellcome Trust/Juvenile Diabetes Research Foundation [061858]
- National Institute of Health Research of England
- Wellcome Trust CIMR
- Medical Research Council
- King Saud bin Abdulaziz University of Health Sciences
- Saudi Ministry for Higher Education
- Juvenile Diabetes Research Foundation International
- National Institute for Health Research Cambridge Biomedical Centre
- government of Rheinland-Pfalz (Stiftung Rheinland Pfalz fur Innovation) [AZ 961-386261/733]
- Johannes Gutenberg-University of Mainz
- Boehringer Ingelheim
- PHILIPS Medical Systems
- Federal Ministry of Education and Research, Germany [A3 01GS0833]
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000M723, BB/I00050X/1, BBS/E/B/0000C151] Funding Source: researchfish
- British Heart Foundation [RG/08/014/24067] Funding Source: researchfish
- Medical Research Council [G0900951, G0800036, G0800784, G0800784B] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G0900729/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10275] Funding Source: researchfish
- BBSRC [BB/I00050X/1, BBS/E/B/0000C151, BBS/E/B/0000M723] Funding Source: UKRI
- MRC [G0800784, G0900951, G0800036] Funding Source: UKRI
- Wellcome Trust [089989/Z/09/Z, 082549/Z/07/Z] Funding Source: Wellcome Trust
The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.
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