Tu204 - The Epigenomic Landscape of CD4 T Cells in Relapsing-remitting Multiple Sclerosis Reveals Drivers of Disease Flare

Abstract Text: Multiple sclerosis (MS) is an autoimmune disease characterized by the destruction of oligodendrocytes in the central nervous system, leading to progressive neurological impairment. The relapsing-remitting form of MS (RRMS) is marked by cycles of inflammatory attacks (flares) and remission periods, driven by CD4+ T cells. While the role of these immune cells is established, the underlying epigenetic changes triggering disease flares remain poorly understood.
To address this, we performed the first comprehensive cross-sectional ATAC-seq analysis comparing the CD4+ T cell epigenomes during RRMS flares and remission. Our integrated approach combined proximal gene assignment and distal regulatory target identification through published cell type-specific Promoter Capture Hi-C data. This provided a more complete view of the disease-relevant genes impacted by dynamic chromatin accessibility changes.
The cross-sectional analysis revealed a genome-wide reduction in chromatin accessibility during flares, particularly affecting anti-inflammatory programs, while pro-inflammatory pathways showed increased activity. Overlapping the differentially accessible regulatory regions (DAR CREs) with MS-associated genetic risk variants helped prioritize the most promising therapeutic targets.
Importantly, Rummagen gene set analysis confirmed significant overlap between our identified DAR CRE networks and previously reported disease-specific and cell type-specific gene signatures. Moreover, our STRING network analysis uncovered novel target genes that showed direct protein-protein interactions with known MS regulators, suggesting their potential as previously unidentified therapeutic candidates.
This cross-sectional epigenomic comparison between RRMS flares and remission offers critical mechanistic insights and highlights both validated and novel regulatory hubs as avenues for future therapeutic intervention.