N6-Methyladenosine Methyltransferase METTL3 Alleviates Diabetes-Induced Testicular Damage through Modulating TUG1/Clusterin Axis

Abstract

Background:The present study investigated the regulatory effects of N 6 -methyladenosine (m6A) methyltransferase like-3 (MET-TL3) in diabetes-induced testicular damage. Methods: In vivo diabetic mice and high glucose (HG) treated GC-1 spg cells were established. The mRNA and protein expressions were determined by real-time quantitative polymerase chain reaction, Western blot, immunofluorescence and immunohistochemistry staining. Levels of testosterone, blood glucose, cell viability, and apoptosis were detected by enzyme-linked immunosorbent assay, MTT, and flow cytometry, respectively. Molecular interactions were verified by RNA immunoprecipitation and RNA pull-down assay. Histopathological staining was performed to evaluate testicular injury. Results: METTL3 and long non-coding RNA taurine up-regulated 1 (lncRNA TUG1) were downregulated in testicular tissues of diabetic mice and HG-treated GC-1 spg cells. METTL3 overexpression could reduce the blood glucose level, oxidative stress and testicular damage but enhance testosterone secretion in diabetic mouse model and HG-stimulated GC-1 spg cells. Mechanically, METTL3-mediated m6A methylation enhanced the stability of TUG1, then stabilizing the clusterin mRNA via recruiting serine and arginine rich splicing factor 1. Moreover, inhibition of TUG1/clusterin signaling markedly reversed the protective impacts of METTL3 overexpression on HG-stimulated GC-1 spg cells. Conclusion:This study demonstrated that METTL3 ameliorated diabetes-induced testicular damage by upregulating the TUG1/ clusterin signaling. These data further elucidate the potential regulatory mechanisms of m6A modification on diabetes-induced testicular injury.

Negative Regulation of LINC01013 by METTL3 and YTHDF2 Enhances the Osteogenic Differentiation of Senescent Pre‐Osteoblast Cells Induced by Hydrogen Peroxide

“…[ 35 ] Notably, METTL3 is able to bind directly to m6A‐modified LINCRTUG1 to enhance the stability of LINCTUG1. [ 45 ] A recent study showed that METTL3 mediates telomeric repeat‐containing RNA m6A modification and promotes its stability via YTHDC1. [ 46 ] In this study, we discovered that METTL3 negatively regulates LINC01013 expression in hFOB1.19 cells.…”

Diabetes and diabetic associative diseases: An overview of epigenetic regulations of TUG1

“…LINC00657, a long non-coding RNA, is gaining prominence for its potential roles in numerous living processes and illnesses. While its precise purposes are still being elucidated, emerging research suggests its involvement in complex cellular pathways ( Bhat et al, 2022a , Bhat et al, 2022b , Bhat et al, 2022c , Trewin et al, 2022 , Tian et al, 2023 , Zhou et al, 2023 ). Investigating LINC00657′s implications could provide valuable insights into its significance, potentially revealing its value as a diagnostic or therapeutic target in various health and disease contexts ( Wang et al, 2019 ).…”

“…This work demonstrates how TUG1/clusterin signalling mediates the amelioration of diabetes-induced testicular damage by METTL3. ( Tian et al, 2023 ).…”