snoRNA <i>Snord3</i> promotes rheumatoid arthritis by epigenetic regulation of ESM1 in fibroblast-like synoviocytes in mice
Jie Huang, Xuekun Fu, Runrun Zhang, Zhuqian Wang, Fang Qiu, Xinxin Chen, Junyu Fan, Chunhao Cao, Yang Xu, Jie Li, Yiying Liang, Dongyi He, Aiping Lü, Chao Liang
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune condition characterized by aggressive fibroblast-like synoviocytes (FLSs). Small nucleolar RNAs (snoRNAs), traditionally implicated in ribosome biogenesis, are now recognized as disease regulators. However, their involvement in RA-FLSs remains poorly understood. Here, we identified small nucleolar RNA, C/D box 3 ( SNORD3 ), a specific snoRNA up-regulated by tumor necrosis factor–α and interleukin-17, as a key driver of the aggressive transformation of RA-FLSs in vitro. Using an FLS-specific aptamer-functionalized siRNA delivery system, we demonstrated that silencing Snord3 alleviated arthritic symptoms in collagen-induced arthritis (CIA) mice. Transcriptome analyses revealed that SNORD3 up-regulated endothelial cell–specific molecule 1 (ESM1) by modulating the polycomb repressive complex 2 (PRC2)–mediated trimethylation of histone H3 at lysine-27 (H3K27me3), driving the aggressive transformation of RA-FLSs. Mechanistically, we found that SNORD3 physically interacted with enhancer of zeste homolog 2 (EZH2) and competitively disrupted the association of EZH2 with retinoblastoma binding protein 4 within PRC2, thus diminishing the H3K27me3 mark on the ESM1 gene promoter to relieve the transcriptional repression of ESM1 . We screened an ESM1-specific aptamer 04 (ESMA04) by systematic evolution of ligands by exponential enrichment, which neutralized ESM1 and inhibited the aggressive transformation of RA-FLSs in vitro. When administered either alone or in combination with a biologic disease-modifying antirheumatic drug, etanercept, ESMA04 demonstrated therapeutic efficacy in CIA mice. Overall, our findings identified SNORD3 -EZH2-ESM1 signaling as a driver of RA-FLS pathogenesis and underscored the promise of aptamer-based therapies for RA treatment.