DNA damage in autoimmunity

Abstract

Rheumatoid arthritis (RA) is the canonical autoimmune disease whose pathogenesis is tightly linked to risk factors which cause damage of DNA and affect immune cell function. DNA damage abnormally reorganizes the genome and triggers deleterious gene transcription. Failure to repair damaged DNA commences the DNA Damage Response (DDR) program marked by metabolic reconditioning, increased proinflammatory cytokine production, oxidative stress, immune cell differentiation. Harmful effects of DDR are transduced partly by chemical modifications on genome packing proteins called histones, and partly by survivin, a potential RA biomarker, already known to bind chromatin. The aim of my thesis is to mechanistically elucidate how these molecular actors encourage DDR and its downstream effects in autoimmunity. A secondary aim was to evaluate if present-day antirheumatic treatment impinges on this mechanism. In Paper 1, I show that survivin binds the histone H3 modifications of trimethylated lysine-4 and lysine-27 in regulatory DNA sequences in CD4+ cells of RA patients. This binding functionally suppresses DNA repair but activates cell cycle, via binding and recruitment of the multiprotein chromatin remodelling BAF complex. Modern anti-rheumatic treatment impacts these pathways and restores DNA repair. In Paper 2, I show that survivin-bound chromatin redirects glucose utilization to meet the energy, and nucleotide demands of the effector CD4+ T cells in RA. Partnering with transcription factors IRF1 and SMAD3, survivin represses TGF/SMAD signaling while activating interferon-sensitive genes. In Paper 3, I provide structural and in vitro evidence that survivin maintains gene transcription by inhibiting the repressive activity of PRC2, the BAF complex antagonist. Paper 4 extends on the survivin-dependent epigenetic mechanism by showing that insulin stimulation redistributes survivin binding to lysine-27 acetylation. This alters activation of important glucose utilization pathways across multiple tissues in RA patients and defines migratory insulin-resistant T cell clusters. Taken together, the investigations conducted in my thesis advance the mechanism of epigenomic control exerted by survivin to drive DDR-related effects in RA pathology. The protein interactome of survivin and the downstream effects of DDR are only partly targeted by modern immunomodulating drugs and require further studies in autoimmunity. Therefore, my thesis offers sufficient evidence to propose a subtype-specific treatment approach, which can identify or predict RA patients responsive to specific treatment when stratified by high expression of survivin, canonical BAF and PRC2 complexes.