Investigating the functional relevance of Fibroblast-like Synoviocytes in Rheumatoid Arthritis using integrated epigenomic datasets and fine-mapping

Abstract

Over 100 genetic associations have been identified for Rheumatoid arthritis (RA) and although the enrichment and functional relevance of these associations in immune cells have been well established in recent literature, the same cannot be said for Fibroblast-like synoviocytes (FLS). This thesis maps the epigenomic landscape of FLS by integrating multi-omics data (ATAC-seq, Hi-C, CHi-C, RNA-seq, ChIP-seq), revealing transcriptionally active regulatory elements across the genome. Cross validation of these multi-omics datasets also revealed their interconnected nature in response to TNF stimulation. The epigenomic landscape of FLS confirms the functional relevance of FLS in RA pathogenesis, by demonstrating that FLS regulatory elements account for up to 24% of RA heritability. By overlapping fine-mapped RA associations with both FLS and publicly available epigenomes, the cell types which are functional active at these associations were identified. This also further refined the list of potential causal variants at each RA association. Each RA association was assigned putative target genes in FLS and immune cells, by providing multi-layered evidence using several multi-omics datasets available: each gene assignment to an association were in 3D proximity to the each other as demonstrated by Hi-C and/or CHi-C, and their activity was confirmed through overlapping analysis with histone modifications of activity (ChIP-seq), assigned genes were also significantly expressed, as demonstrated by RNA-seq. Overall, the results presented provide RA associated genes for further study/validation, and a useful resource for future epigenetic studies into FLS.

Date of Award	31 Dec 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andrew Morris (Supervisor), Stephen Eyre (Supervisor) & Paul Martin (Supervisor)