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Chromatin-based techniques map DNA interaction landscapes in psoriasis susceptibility loci and highlight KLF4 as a target gene in 9q31

By Helen Ray-Jones, Kate Duffus, Amanda McGovern, Paul Martin, Chenfu Shi, Jenny Hankinson, Oliver Gough, Andrew P Morris, Antony Adamson, Christopher Taylor, James Ding, Vasanthi Priyadarshini Gaddi, Yao Fu, Patrick Gaffney, Gisela Orozco, Richard B Warren, Steve Eyre

Posted 30 Oct 2019
bioRxiv DOI: 10.1101/822304

Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. Here, we use a disease-focused Capture Hi-C experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. In the 9q31 risk locus we combine further epigenomic evidence to demonstrate how the psoriasis association forms a functional interaction with the distant (>500 kb) KLF4 gene. We use CRISPR activation coupled with RNA-seq to demonstrate how activation of psoriasis-associated enhancers upregulates KLF4 in HaCaT cells. Our study design provides a robust pipeline for following up on GWAS disease-associated variants, paving the way for functional translation of genetic findings into clinical benefit.

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