title: 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells.
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+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+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.
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Benjamin Joachim
authors.initials: BJ
authors.lastname: Schmiedel
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Grégory
authors.initials: G
authors.lastname: Seumois
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Samaniego-Castruita
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Cayford
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Veronique
authors.initials: V
authors.lastname: Schulten
authors.affiliation: German Cancer Research Center (DKFZ), Division of Pediatric Neurooncology, 69120 Heidelberg, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Chavez
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Ferhat
authors.initials: F
authors.lastname: Ay
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.|Clinical and Experimental Sciences, National Institute for Health Research Southampton Respiratory Biomedical Research Unit, University of Southampton, Faculty of Medicine, Southampton SO16 6YD, UK.
authors.forename: Pandurangan
authors.initials: P
authors.lastname: Vijayanand
mesh_terms: D001249:Asthma / Q000235:genetics* / Q000276:immunology*; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D000076246:CCCTC-Binding Factor / Q000378:metabolism*; D002478:Cells, Cultured; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D007438:Introns / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012307:Risk Factors; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D007376:Interleukin-2