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17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells

17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells
17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells

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.

Journal Article
13426
Schmiedel, Benjamin Joachim
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Seumois, Grégory
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Samaniego-Castruita, Daniela
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Cayford, Justin
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Schulten, Veronique
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Chavez, Lukas
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Ay, Ferhat
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Sette, Alessandro
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Peters, Bjoern
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Vijayanand, Pandurangan
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Schmiedel, Benjamin Joachim
ba8ead04-6642-48b4-b4a6-b96910e17fab
Seumois, Grégory
0a7444d5-a537-45c2-adfc-fe1c32f2c37d
Samaniego-Castruita, Daniela
e0925b0f-9b07-46e3-a433-08a941e11c6f
Cayford, Justin
11060511-cd03-4dc0-b450-ff711200f4ef
Schulten, Veronique
d896b490-2f8f-49c2-9c7a-5a6eefa343eb
Chavez, Lukas
84f58e4d-a3e4-4b69-87d4-5783f15580cb
Ay, Ferhat
c43aed4d-b4ea-4206-9a2b-520e0ed75ae7
Sette, Alessandro
240988b3-3c05-4041-a39b-8be8e145803c
Peters, Bjoern
c49863c8-d2c6-4db4-9d2c-72a7c0cbe117
Vijayanand, Pandurangan
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Schmiedel, Benjamin Joachim, Seumois, Grégory, Samaniego-Castruita, Daniela, Cayford, Justin, Schulten, Veronique, Chavez, Lukas, Ay, Ferhat, Sette, Alessandro, Peters, Bjoern and Vijayanand, Pandurangan (2016) 17q21 asthma-risk variants switch CTCF binding and regulate IL-2 production by T cells. Nature Communications, 7, 13426. (doi:10.1038/ncomms13426).

Record type: Article

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.

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Accepted/In Press date: 3 October 2016
e-pub ahead of print date: 16 November 2016
Published date: 16 November 2016
Keywords: Journal Article

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Local EPrints ID: 412149
URI: https://eprints.soton.ac.uk/id/eprint/412149
PURE UUID: 96c51a2a-e491-4291-88b3-ac1ba4c7a248

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Date deposited: 11 Jul 2017 16:32
Last modified: 28 May 2019 16:34

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Contributors

Author: Benjamin Joachim Schmiedel
Author: Grégory Seumois
Author: Daniela Samaniego-Castruita
Author: Justin Cayford
Author: Veronique Schulten
Author: Lukas Chavez
Author: Ferhat Ay
Author: Alessandro Sette
Author: Bjoern Peters
Author: Pandurangan Vijayanand

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