METTL3 Is Involved in the Development of Graves’ Disease by Inducing SOCS mRNA m6A Modification

Abstract

ObjectiveEpigenetic modifications in RNA are known to play critical roles in cell differentiation through regulating expressions of some key genes including members of the suppressor of cytokine signaling (SOCS) family. The present study aimed to unveil the relationship of SOCS mRNA methylation induced by methyltransferase like 3 (METTL3) with Graves’ disease (GD).MethodsDifferently expressed genes (DEG) in GD tissues were identified using microarray analysis and further validated using CD4+ T cell microarray of GD tissues and isolated peripheral blood mononuclear cells (PBMCs). Furthermore, expressions of METTL3 targeted genes were detected using METTL3 knock-down experiment in RAW264.7 cells.ResultsHigh throughput microarrays revealed that METTL3 and SOCS molecules were aberrantly expressed in thyroid tissues and CD4+T cells of GD compared to the controls. Bioinformatic analysis was undertaken by searching databases of found genes of the SOCS family that possessed many mRNA m6A modification loci. METTL3 knock-down experiment revealed that expressions of SOCS family members SOCS1, SOCS2, SOCS4, SOCS5, and SOCS6 were increased after METTL3 knock-down.ConclusionsFor the first time, the present study revealed the relationship between m6A modification and GD and indicated that METTL3 may be involved in the development of GD by inducing mRNA m6A methylation modification of SOCS family members.

Sequential inspiratory muscle exercise-noninvasive positive pressure ventilation alleviates oxidative stress in COPD by mediating SOCS5/JAK2/STAT3 pathway

“…The above reports further confirm our conjecture that SOCS5/JAK2/STAT3 signaling may be involved in the occurrence and development of COPD by influencing oxidative stress levels. Besides, the alteration of SOCS5 in diseases was confirmed to be related various regulation such as miRNAs sponge, DNA methylation, m6A modification and transcription regulation [ 46 , 48 , 53 ], and these regulatory pathways were acted an important role in COPD pathogenesis [ 54 – 56 ]. Thus, it was implied that the exact mechanism of abnormally expressed SOCS5 in COPD was worthy of research.…”

Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study

“…335 Besides, methyltransferase-like 3 (METTL3) is participated in the pathogenesis of GD by inducing m6A modification of SOCS family mRNA. 336 As a common complication of GD, Graves' ophthalmopathy (GO) involves hypermethylation genes associated with inflammation and hypomethylated genes related to autoimmunity in orbital fibroblasts. 337,338 HDAC4 is participated in the pathogenesis of GO by facilitating proliferation and extracellular matrix production in orbital fibroblasts.…”

M6A methylation modification in autoimmune diseases, a promising treatment strategy based on epigenetics

“…Through a high-throughput microarray, METTL3 and cytokine signaling (SOCS) molecules were abnormally expressed in the CD4 T cells of Graves' disease. After METTL3 knockdown, the expression of some factors of SOCS family members increased [ 79 ]. Inducing m6A methylation in members of the SOCS family is the mechanism by which METTL3 is involved in the development of Graves' disease.…”

“… [ 72 ] Graves’Disease METTL3 Writer CD4T cells Down-regulation Induces SOCS mRNA m6A modification. [ 79 ] MS ALKBH5 Eraser T cells Up-regulation Controls CD4 T cell pathogenicity. [ 89 ] Uveitis FTO Eraser EAU mouse RPE cells Down-regulation Regulates the m6A level of ATF4 to affect the translation of ATF4 and the expression of inflammatory factors.…”