Dissection of a non-coding risk locus at 1p36.23 identifiesERRFI1as a novel gene in the pathogenesis of psoriasis and psoriatic arthritis

Abstract

AbstractBackgroundPsoriasis and its associated inflammatory arthritis Psoriatic Arthritis (PsA) are potentially life-ruining conditions associated with numerous comorbidities. A previously-identified genetic risk association for psoriasis and PsA lies in a non-coding region at chromosome 1p36.23, and as such functional validation is required to determine the genetic mechanism contributing to psoriatic disease risk.Resultsrs11121131 – a variant in tight linkage with rs11121129, the lead GWAS variant for the 1p36.23 association – lies in a putative enhancer active in keratinocytes but not in immune cells. Promoter-capture Hi-C and H3K27Ac HiChIP showed keratinocyte-specific interactions between 1p36.23 and theTNFRSF9/PARK7/ERRFI1gene locus ∼200Kb upstream of the risk locus. Deletion of the enhancer in HaCat keratinocytes led to a reduction in transcript levels of the geneERRFI1, a negative regulator of Epidermal Growth Factor Receptor (EGFR) signalling. CRISPR activation of the enhancer also affectedERRFI1levels, but paradoxically showed that steady-state activation led to repression ofERRFI1, accompanied by significant deposition of H3K27Me3 histone marks at both the enhancer and theERRFI1gene locus. ERRFI1 levels were shown to be increased in inflamed skin from a mouse model of psoriasis, further suggesting its involvement in disease.ConclusionsThese data indicate rs11121131 lies in an enhancer which modulatesERRFI1expression in keratinocytes, providing a likely risk mechanism for the 1p36.23 risk association.ERRFI1represents a novel gene in the pathogenesis of psoriasis and PsA – improving our understanding of these diseases – and the ERRFI1/EGFR signalling axis may therefore be a target for new treatment modalities for psoriatic disease.