TY - JOUR
T1 - Chromatin Looping Links Target Genes with Genetic Risk Loci for Dermatological Traits
AU - Shi, Chenfu
AU - Ray-Jones, Helen
AU - Ding, James
AU - Duffus, Kate
AU - Fu, Yao
AU - Gaddi, Vasanthi Priyadarshini
AU - Gough, Oliver
AU - Hankinson, Jenny
AU - Martin, Paul
AU - McGovern, Amanda
AU - Yarwood, Annie
AU - Gaffney, Patrick
AU - Eyre, Steve
AU - Rattray, Magnus
AU - Warren, Richard B
AU - Orozco, Gisela
N1 - Funding Information:
The authors would like to acknowledge the assistance given by Information Technology Services and the use of the Computational Shared Facility at The University of Manchester, United Kingdom. This work was funded by the Wellcome Trust (award references 207491/Z/17/Z and 215207/Z/19/Z ), the Versus Arthritis (award reference 21754 ), the NIHR Manchester Biomedical Research Centre , and the Medical Research Council (award reference MR/N00017X/1 ).
Funding Information:
The authors would like to acknowledge the assistance given by Information Technology Services and the use of the Computational Shared Facility at The University of Manchester, United Kingdom. This work was funded by the Wellcome Trust (award references 207491/Z/17/Z and 215207/Z/19/Z), the Versus Arthritis (award reference 21754), the NIHR Manchester Biomedical Research Centre, and the Medical Research Council (award reference MR/N00017X/1). Conceptualization: SE, RBW, GO, MR, CS, HRJ; Data curation: CS, HRJ, PM, VPG; Formal Analysis: CS; Funding Acquisition: GO, MR, RBW, SE; Investigation: CS, HRJ, JH; Methodology: OG, JH, PM, AMG, AY, PG, YF, KD, JD; Project Administration: RBW, SE, GO; Resources: VPG, PM, PG, YF, GO, SE, MR, RBW; Software: CS; Supervision: GO, MR, SE, RBW; Writing – Original Draft Preparation: CS, HRJ, JD; Writing – Review and Editing: CS, HRJ, JD, KD, YF, VPG, OG, JH, PM, AM, AY, PG, SE, MR, RBW, GO
Publisher Copyright:
© 2021 The Authors
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Chromatin looping between regulatory elements and gene promoters presents a potential mechanism whereby disease risk variants affect their target genes. In this study, we use H3K27ac HiChIP, a method for assaying the active chromatin interactome in two cell lines: keratinocytes and skin lymphoma-derived CD8+ T cells. We integrate public datasets for a lymphoblastoid cell line and primary CD4+ T cells and identify gene targets at risk loci for skin-related disorders. Interacting genes enrich for pathways of known importance in each trait, such as cytokine response (psoriatic arthritis and psoriasis) and replicative senescence (melanoma). We show examples of how our analysis can inform changes in the current understanding of multiple psoriasis-associated risk loci. For example, the variant rs10794648, which is generally assigned to IFNLR1, was linked to GRHL3, a gene essential in skin repair and development, in our dataset. Our findings, therefore, indicate a renewed importance of skin-related factors in the risk of disease.
AB - Chromatin looping between regulatory elements and gene promoters presents a potential mechanism whereby disease risk variants affect their target genes. In this study, we use H3K27ac HiChIP, a method for assaying the active chromatin interactome in two cell lines: keratinocytes and skin lymphoma-derived CD8+ T cells. We integrate public datasets for a lymphoblastoid cell line and primary CD4+ T cells and identify gene targets at risk loci for skin-related disorders. Interacting genes enrich for pathways of known importance in each trait, such as cytokine response (psoriatic arthritis and psoriasis) and replicative senescence (melanoma). We show examples of how our analysis can inform changes in the current understanding of multiple psoriasis-associated risk loci. For example, the variant rs10794648, which is generally assigned to IFNLR1, was linked to GRHL3, a gene essential in skin repair and development, in our dataset. Our findings, therefore, indicate a renewed importance of skin-related factors in the risk of disease.
KW - Cell Line, Tumor
KW - Chromatin/genetics
KW - Chromatin Assembly and Disassembly/genetics
KW - DNA-Binding Proteins/genetics
KW - Datasets as Topic
KW - Enhancer Elements, Genetic
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Linkage Disequilibrium
KW - Polymorphism, Single Nucleotide
KW - Promoter Regions, Genetic
KW - Quantitative Trait Loci
KW - Receptors, Interferon/genetics
KW - Skin Diseases/genetics
KW - Transcription Factors/genetics
U2 - 10.1016/j.jid.2021.01.015
DO - 10.1016/j.jid.2021.01.015
M3 - Article
C2 - 33607115
VL - 141
SP - 1975
EP - 1984
JO - The Journal of Investigative Dermatology
JF - The Journal of Investigative Dermatology
SN - 0022-202X
IS - 8
ER -