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17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells.
- Source :
-
Nature communications [Nat Commun] 2016 Nov 16; Vol. 7, pp. 13426. Date of Electronic Publication: 2016 Nov 16. - Publication Year :
- 2016
-
Abstract
- Asthma and autoimmune disease susceptibility has been strongly linked to genetic variants in the 17q21 haploblock that alter the expression of ORMDL3; however, the molecular mechanisms by which these variants perturb gene expression and the cell types in which this effect is most prominent are unclear. We found several 17q21 variants overlapped enhancers present mainly in primary immune cell types. CD4 <superscript>+</superscript> T cells showed the greatest increase (threefold) in ORMDL3 expression in individuals carrying the asthma-risk alleles, where ORMDL3 negatively regulated interleukin-2 production. The asthma-risk variants rs4065275 and rs12936231 switched CTCF-binding sites in the 17q21 locus, and 4C-Seq assays showed that several distal cis-regulatory elements upstream of the disrupted ZPBP2 CTCF-binding site interacted with the ORMDL3 promoter region in CD4 <superscript>+</superscript> T cells exclusively from subjects carrying asthma-risk alleles. Overall, our results suggested that T cells are one of the most prominent cell types affected by 17q21 variants.
- Subjects :
- B-Lymphocytes metabolism
Base Sequence
Binding Sites genetics
Cells, Cultured
Enhancer Elements, Genetic genetics
Humans
Introns genetics
Promoter Regions, Genetic genetics
Protein Binding
Risk Factors
Asthma genetics
Asthma immunology
CCCTC-Binding Factor metabolism
Chromosomes, Human, Pair 17 genetics
Genetic Predisposition to Disease
Interleukin-2 biosynthesis
Polymorphism, Single Nucleotide genetics
T-Lymphocytes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 7
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 27848966
- Full Text :
- https://doi.org/10.1038/ncomms13426