Characterising a Novel Therapeutic Target for Psoriasis, TYK2, Using Functional Genomics.

Psoriasis (Ps) is a debilitating immune-mediated chronic skin condition. It affects about 1-3% of the world population, with an 8-11% prevalence in Northern European populations. Tyrosine kinase 2 (TYK2) is a newly identified target for Ps. An independent non-coding genetic association with Ps has been identified ~400 kb upstream of TYK2. The variants making up the credible Ps Single-Nucleotide Polymorphism (SNP) set were identified in their genomic context with the potential to influence TYK2 expression by interacting with regulatory elements involved in gene regulation. Previous evidence from our laboratory has suggested that credible SNP sets in intronic regions can be distal regulators of the genes of interest through long-range chromatin interactions. We hypothesise that SNPs at ILF3 are distal regulators of TYK2 expression via long-range chromatin interactions and Ps risk. The dysregulation of the TYK2 pathway in Ps may be mediated by a combination of GWAS risk SNPs at ILF3 and TYK2 and downstream genes. We investigated this by employing functional genomics and molecular biology methods. We developed a CD4 T cell model system with Jurkat-dCAS9-VP64 and Jurkat-dCAS9-KRAB cells using CRISPR activation and CRISPR inhibition of the risk variants rs892086 and rs7248205, selected from the latest Ps GWAS SNP set for their long-range interaction and light Linkage Disequilibrium (R