Project Summary Fibroblast-like synoviocytes (FLS) play a critical role in the pathology of inflammatory joint diseases such as rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis. Under chronic inflammation, FLS undergo epigenetic remodeling and are transformed into aggressive cancer-like cells, which evade apoptosis, proliferate, and produce catabolic factors that degrade the articular cartilage and subchondral bone. Once, transformed, the FLS are known to retain their aggressive properties despite removing them from the inflammatory microenvironment. Epigenetic remodeling is suggested as the underlying cause for the persistently transformed phenotype of the FLS. However, the identity of the factors that drive the epigenetic remodeling of the FLS is incompletely understood. In this proposal, we will focus on defining the roles of an epigenetic hub protein SETBP1 (Set binding protein 1) in regulating the switch from a homeostatic epigenomic signature to an arthritic epigenomic signature of the FLS. SETBP1 is an epigenetic hub protein that recruits various types of histone remodeling complexes to activate or repress gene expression. Previous studies show that gain-of-function and loss-of-function mutations or deletions of SETBP1 result in impaired embryogenesis and skeletogenesis. Our preliminary data suggest that SETBP1 also plays a role in maintaining the homeostasis of FLS in adult joints. Based on these findings we propose our overarching hypothesis that the downregulation of SETBP1 promotes joint degeneration in IJD. We propose that SETBP1 acts as an epigenetic switch by repressing pro-inflammatory genes and by repressing anti-inflammatory gene expression. We will test this hypothesis by the conditional inactivation of Setbp1 in adult joints in a mouse model of rheumatoid arthritis. In Aim 1 we will use phenotypic and molecular analysis to show a negative interaction between the inflammation and SETBP1. Under Aim 2 we will investigate if the level of SETBP1 protein determines the epigenetic status of the FLS and thereby drives their transformation. Under Aim 3 we will investigate the upstream molecular mechanism for SETBP1 expression. Successful completion of this proposal will establish SETBP1 as an epigenetic switch factor in the FLS. Our results will suggest that SETBP1 is a therapeutic target to prevent drug resistance and the recurrence of symptoms in autoimmune joint diseases.