Mapping DNA interaction landscapes in psoriasis susceptibility loci highlights KLF4 as a target gene in 9q31

Helen Ray-Jones, Kate Duffus, Amanda Mcgovern, Paul Martin, Chenfu Shi, Jenny Hankinson, Oliver Gough, Annie Yarwood, Andrew Morris, Antony Adamson, Christopher Taylor, James Ding, Vasanthipriyadarshini Gaddi, Yao Fu, Patrick Gaffney, Gisela Orozco, Richard Warren, Stephen Eyre

Research output: Contribution to journalArticlepeer-review


Background 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. This is largely a result of the findings that over 90% of GWAS variants map outside of protein-coding DNA, and instead are enriched in cell type and stimulation-specific gene regulatory regions. Results Here, we use a disease-focused Capture Hi-C (CHi-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. For one locus, uniquely, we combine further epigenomic evidence to demonstrate how a psoriasis-associated region forms a functional interaction with the distant (>500 kb) KLF4 gene. This interaction occurs between the gene and active enhancers in HaCaT cells, but not in My-La cells. We go on to investigate this long-distance interaction further with Cas9 fusion protein-mediated chromatin modification (CRISPR activation) coupled with RNA-seq, demonstrating how activation of the psoriasis associated enhancer upregulates KLF4 and its downstream targets, relevant to skin cells and apoptosis. Conclusions This approach utilises multiple functional genomic techniques to follow up GWAS associated variants implicating relevant cell types and causal genes in each locus; these are vital next steps for the translation of genetic findings into clinical benefit.
Original languageEnglish
Article number47
JournalBMC Biology
Issue number1
Publication statusPublished - 4 May 2020


  • psoriasis
  • chromatin
  • GWAS
  • CHi-C
  • HiChIP
  • KLF4


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