The critical role of m 6 A methylation in the pathogenesis of Graves' ophthalmopathy
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RESEARCH
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The critical role of m6A methylation in the pathogenesis of Graves' ophthalmopathy Li Zhu1†, Siyan Li1†, Shikun He1, Qizhe Tong1, Lejin Wang1, Xiaohua Li2, Xi Wu1, Qingyu Meng1, Enzhong Jin1, Chuan Zhang1, Tianyuan Li1, Ningda Xu1, Lvzhen Huang1, Yi Wang1* and Mingwei Zhao1*
Abstract Purpose: To investigate the role of N6-methyladenosine (m6A) RNA modification in the pathogenesis of Graves' ophthalmopathy (GO). Methods: Surgically excised extraocular muscles from 7 patients with GO and 5 subjects without GO were used. The global m6A levels in the specimens were determined using an m6A RNA methylation quantification kit. RNA sequencing (RNA-seq) was used to analyze the molecules involved in the regulation of m6A RNA methylation and the differential expression of mRNAs between the two groups (4 eyes, respectively). The expression of m6A RNA modification genes was evaluated by real-time PCR. The functional implications of the gene alterations between the GO and control specimens were determined by Gene Ontology analysis. Results: The m6A level was significantly increased in the specimens of GO patients compared to the control specimens (P < 0.05). The expression of m6A methylation regulators, such as WT1 associated protein (WTAP), alkylation repair homolog protein 5 (ALKBH5), E74 like ETS transcription factor 3 (ELF3), YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), YTHDF3 and YTH domain containing 2 (YTHDC2), was significantly upregulated (P < 0.05). Gene Ontology enrichment analysis showed that the most highly upregulated genes and biological pathways were related to the immune response and inflammatory processes such as lymphocyte activation, leukocyte differentiation, cytokine production and cytokine-mediated signaling pathways. Conclusions: Our results suggest that m6A methylation may play a critical role in the pathogenesis of GO and that targeting genes that regulate m6A methylation may provide a new therapeutic approach for GO. Keywords: m6A methylation, Graves' ophthalmopathy, Pathogenesis, RNA-seq
Background Graves' ophthalmopathy (GO), also called thyroid eye disease (TED), is the most significant extrathyroidal manifestation of Graves' disease patients. The clinical manifestations of GO result largely from immune and inflammatory * Correspondence: [email protected]; [email protected] † Li Zhu and Siyan Li contributed equally to this paper and are co-first authors. 1 Department of Ophthalmology, Peking University People’s Hospital, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry, Peking University Health Science Center, Xizhimen South Street 11, Xi Cheng District, Beijing 100044, China Full list of author information is available at the end of the article
responses within the orbit. The pathological process is recognized to be driven by cellular and humoral immunity and inflammation, which stimulate retroocular fibroblast proliferation, local adipogenesis and the inflammatory resp
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