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bioRxiv · 10.1101/2020.03.05.973271

An active chromatin interactome elucidates the biological mechanisms underlying genetic risk factors of dermatological conditions in disease relevant cell lines

Shi, C.·Ray-Jones, H.·Ding, J.·Duffus, K.·Fu, Y.·Gaddi, V. P.·Gough, O.·Hankinson, J.·Martin, P.·Mcgovern, A.·Yarwood, A.·Gaffney, P.·Eyre, S.·Rattray, M.·Warren, R.·Orozco, G.
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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. O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/973271v2_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@99cd40org.highwire.dtl.DTLVardef@1725b6dorg.highwire.dtl.DTLVardef@d05d21org.highwire.dtl.DTLVardef@1924d07_HPS_FORMAT_FIGEXP M_FIG 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. C_FIG

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Shi, C., Ray-Jones, H., Ding, J., Duffus, K., Fu, Y., Gaddi, V. P., Gough, O., Hankinson, J., Martin, P., Mcgovern, A., Yarwood, A., Gaffney, P., Eyre, S., Rattray, M., Warren, R., Orozco, G.. 2020-03-06. An active chromatin interactome elucidates the biological mechanisms underlying genetic risk factors of dermatological conditions in disease relevant cell lines. https://doi.org/10.1101/2020.03.05.973271

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