Wellcome Trust Joint Basic and Clinical PhD Programme at the University of Birmingham (360G-Wellcome-097438_Z_11_Z)

Synovial fibroblasts (RA SFb) drive disease persistence and joint destruction in RA. They are characterised by a persistent in vitro invasive phenotype. It is not known how or when this phenotype is generated during the evolution of RA, but preliminary work suggests that epigenetic modifications play an important role. Increasing evidence for a therapeutic early window in the first few months of RA implies that such modifications may not be fully established early in disease. We will test the hypothesis that the persistent RA SFb phenotype is determined by epigenetic regulation of gene transcription and that epigenetic marks will differ in fibroblasts from patients in different outcome groups in the very early stages of inflammatory arthritis. Objectives: To compare transcriptional profiles of SFb from patients in four different clinical outcome groups (very early arthritis that becomes RA, very early arthritis that resolves, established RA, normal) To determine the genome wide presence of histone marks of stable gene activation (H3K4me3) and repression (H2K27me3) in SFb from patients in those four groups To correlate the presence of activating and repressing histone marks with gene expression To explore the functional significance of these findings using gene ontology and pathway analyses, and in vivo functional assays