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An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

View ORCID ProfileChenfu Shi, View ORCID ProfileHelen Ray-Jones, View ORCID ProfileJames Ding, Kate Duffus, Yao Fu, Vasanthi Priyadarshini Gaddi, View ORCID ProfileOliver Gough, View ORCID ProfileJenny Hankinson, View ORCID ProfilePaul Martin, View ORCID ProfileAmanda McGovern, View ORCID ProfileAnnie Yarwood, Patrick Gaffney, View ORCID ProfileSteve Eyre, View ORCID ProfileMagnus Rattray, Richard B Warren, View ORCID ProfileGisela Orozco
doi: https://doi.org/10.1101/2020.03.05.973271
Chenfu Shi
1Centre for Genetics and Genomics Versus Arthritis. Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
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Helen Ray-Jones
1Centre for Genetics and Genomics Versus Arthritis. Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
2Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester, UK
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James Ding
1Centre for Genetics and Genomics Versus Arthritis. Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
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Kate Duffus
1Centre for Genetics and Genomics Versus Arthritis. Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
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Yao Fu
3Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, 73104, OK, USA
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Vasanthi Priyadarshini Gaddi
1Centre for Genetics and Genomics Versus Arthritis. Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
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Oliver Gough
1Centre for Genetics and Genomics Versus Arthritis. Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
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Jenny Hankinson
4Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester, UK
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Paul Martin
1Centre for Genetics and Genomics Versus Arthritis. Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
5The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
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Amanda McGovern
1Centre for Genetics and Genomics Versus Arthritis. Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
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Annie Yarwood
1Centre for Genetics and Genomics Versus Arthritis. Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
2Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester, UK
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Patrick Gaffney
3Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, 73104, OK, USA
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Steve Eyre
1Centre for Genetics and Genomics Versus Arthritis. Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
6NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
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Magnus Rattray
7Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK
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Richard B Warren
2Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester, UK
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Gisela Orozco
1Centre for Genetics and Genomics Versus Arthritis. Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK
6NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
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  • For correspondence: gisela.orozco@manchester.ac.uk
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Abstract

Chromatin looping between regulatory elements and gene promoters presents a potential mechanism whereby disease risk variants affect their target genes. Here we use H3K27ac HiChIP, a method for assaying the active chromatin interactome in two cell lines: keratinocytes and skin 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, 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 in our dataset, a gene essential in skin repair and development. Our findings, therefore, indicate a renewed importance of skin related factors in the risk of disease.

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Graphical Abstract

In this article we take disease associated variants from 5 dermatological conditions and use cell type specific datasets to map genes that could be affected by these variants, providing insight into disease mechanisms.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits
Chenfu Shi, Helen Ray-Jones, James Ding, Kate Duffus, Yao Fu, Vasanthi Priyadarshini Gaddi, Oliver Gough, Jenny Hankinson, Paul Martin, Amanda McGovern, Annie Yarwood, Patrick Gaffney, Steve Eyre, Magnus Rattray, Richard B Warren, Gisela Orozco
bioRxiv 2020.03.05.973271; doi: https://doi.org/10.1101/2020.03.05.973271
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An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits
Chenfu Shi, Helen Ray-Jones, James Ding, Kate Duffus, Yao Fu, Vasanthi Priyadarshini Gaddi, Oliver Gough, Jenny Hankinson, Paul Martin, Amanda McGovern, Annie Yarwood, Patrick Gaffney, Steve Eyre, Magnus Rattray, Richard B Warren, Gisela Orozco
bioRxiv 2020.03.05.973271; doi: https://doi.org/10.1101/2020.03.05.973271

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