FRI0004 CHROMATIN INTERACTIONS IN NOVEL CELL TYPES REVEAL PARK7 AND ERRFI1 AS PUTATIVE CAUSAL GENES IN THE SUSCEPTIBILITY TO PSORIATIC ARTHRITIS. (June 2019)

• Record Type: Journal Article
• Authors: Gough, Oliver; Ray-Jones, Helen; Martin, Paul; Bowes, John; Adamson, Antony; Barton, Anne; Warren, Richard B.; Eyre, Stephen
• Is Part Of: Annals of the rheumatic diseases. Volume 78(2019)Supplement 2
• Page Start: 663
• Page End: 663
• Publication Date: 2019-06
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2019-eular.6272
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: One of the major tasks post-GWAS is to link disease associated single nucleotide polymorphisms (SNPs) to their causal genes. Unexpectedly the vast majority of disease associated SNPs lay outside protein coding regions of the genome, often in gene regulatory regions, known as enhancers. These enhancers operate by physically interacting with their target genes, often over long distance, and often skipping genes. We, and others, have demonstrated how these enhancer interactions can change with different cell type and stimulatory conditions. In psoriatic arthritis, as with all complex diseases, there are a large number of genetic loci implicated in susceptibility to disease, but relatively few of these regions have confirmed causal genes. Objectives: Map disease associated enhancers to potential causal genes through physical chromatin interactions in relevant, novel cell types. Methods: We used Capture HiC (CHi-C) technology to map enhancer to promoter interactions in both a keratinocyte cell line (HaCaT) and a T cell line (MyLa) in biological duplicate. We generated Hi-C libraries and enriched them for autoimmune-associated GWAS loci using RNA baits. The resultant CHi-C libraries underwent high-throughput sequencing generating 75 bp paired-ends. Significant interactions were detected using CHiCAGO. Results: A region on chromosome 1p36 demonstrated markedly differential interactions between the T cell line (MyLa) and the skin cell line (HaCat). Here the enhancer region containing SNPs associated with PsA demonstrated a strong interaction with both the PARK7 and ERRFI1 genes in HaCaT cells, absent in the MyLa cell line (fig 1 ). These interactions were contained within a functionally relevant topological activation domain (TAD) boundary, enriched for enhancer to promoter links. Bioinformatic analysis demonstrated how a SNP highly correlated with the PsA lead variant is found within an open, active region of chromatin in the HaCaT cell line, shifting the priority from the (statistical) lead variant (rs11121129) to rs11121131 – demonstrating the value of this type of analysis (fig 2 ). Conclusion: A region associated with PsA on chromosome 1p36, previously annotated with the TNFSF9/ERRFI1/SLC45A1 gene, makes robust interactions with the PARK7 and ERRFI1 genes, both strong candidates for causality in disease. An associated variant, within a cell type relevant enhancer, is currently being targeted with genome editing technology (CRISPR) to assess its potential for causality and possible mechanism. Disclosure of Interests: Oliver Gough: None declared, Helen Ray-Jones: None declared, Paul Martin: None declared, John Bowes: None declared, Antony Adamson: None declared, Anne Barton: None declared, Richard B. Warren Grant/research support from: AbbVie, Almirall, Amgen, Celgene, Janssen, Lilly, LEO, Novartis, Pfizer, UCB Pharma, Consultant for: AbbVie, Almirall, Amgen, Boehringer-Ingleheim, Celgene, Janssen, LEO, Lilly, Novartis, Pfizer, Sanofi, UCB, Xenoport, Stephen Eyre: None declared