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Surveying the epigenetic landscape of murine synovitis to explore the heterogeneity of rheumatoid arthritis

Hughes, Stuart 2023. Surveying the epigenetic landscape of murine synovitis to explore the heterogeneity of rheumatoid arthritis. PhD Thesis, Cardiff University and Monash University.
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Rheumatoid arthritis, an immune-mediated inflammatory disease, attacks joints, causing cartilage, bone erosion and chronic pain. Despite significant advances treatment options, many patients do not respond to commonly prescribed targeted therapies, necessitating improvements in their stratification. Ultrasound-directed biopsies of inflamed joints show the clinical presentation of synovitis is highly heterogeneous, with histological features identifying fibroblast-rich, myeloid-rich, and lymphoid-rich synovitis. The focus of my thesis is to understand the mechanisms driving these alternate patterns of disease. To explore how these forms of synovitis evolve, I applied analytical methods to survey the epigenetic landscape of inflamed joint tissues from mice with antigen-induced arthritis (AIA). Experiments were conducted in wild-type (Wt) mice and mice deficient in the a-receptor subunit for either interleukin-6 (Il6ra-/- ) or interleukin-27 (Il27ra-/-), which develop hallmarks of synovitis resembling myeloid-rich, fibroblast-rich, and lymphoid-rich synovitis respectively. Next-generation sequencing methods assessing chromatin accessibility (ATACseq) and transcription factor (ChIP-seq) involvement in synovitis were generated and mapped against synovial RNA-seq datasets previously generated from these mice. Considering the biology of IL-6 and IL-27, my analysis focussed on the role of the Janusactivated kinase-Signal Transducer and Activator of Transcription (Jak-STAT) pathway and the STAT1 and STAT3 transcription factors. Analysis of synovial tissues from mice with AIA identified elements of gene regulation common to all three strains with AIA and others unique to Wt, Il6ra-/- and Il27ra-/- mice. In this regard, ATAC-seq revealed subtle differences in the epigenetic control of gene expression specific to each synovial pathotype. Building on these findings, I next evaluated the role of STAT1 and STAT3, which share a complex regulatory interplay affecting alternate patterns of gene regulation. My results confirmed the importance of this mechanism in determining synovitis in mice with AIA, with STAT1 and STAT3 effecting processes including leukocyte recruitment and activation, pannus formation and joint damage. Here, molecular pathway analysis identified genomic signatures linked with disease heterogeneity in synovitis, highlighting the role of chromatin accessibility and transcription factor activity in shaping the course of disease. My results open opportunities to consider the pathways driving arthritis progression and clinical responses to biological medicines commonly used in treating rheumatoid arthritis.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 19 April 2024
Last Modified: 19 Apr 2024 13:11

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