Abstract
PurposeTo investigate the role of N6-methyladenosine (m6A) RNA modification in the pathogenesis of Graves' ophthalmopathy (GO).MethodsSurgically 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.ResultsThe 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.ConclusionsOur 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.
Highlights
Graves' ophthalmopathy (GO), called thyroid eye disease (TED), is the most significant extrathyroidal manifestation of Graves' disease patients
WT1 associated protein (WTAP) was significantly upregulated in GO extraocular muscles (EOMs) compared with control EOMs (P < 0.05, Fig. 1b)
No significant difference in the expression of FTO and ALKBH5 was observed between EOMs from patients with GO and control subjects
Summary
Graves' ophthalmopathy (GO), called thyroid eye disease (TED), is the most significant extrathyroidal manifestation of Graves' disease patients. Accumulating evidence suggests that epigenetic factors may be involved in the pathogenesis of Graves' disease (2020) 7:55. The idea that epigenetic factors contribute to the pathogenesis of GD is further supported by a report showing global abnormalities in histone methylation and histone deacetylation in patients with GD [2, 3]. These results suggest that epigenetic modifications contribute to the pathogenesis of both GD and GO; the involvement of RNA methylation in the pathogenesis of GD components, GO, has not been reported
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