Comprehensive Analysis of N6-Methyladenosine Modification Profiling in Diabetic Erectile Dysfunction

Diabetic erectile dysfunction (DMED) is a prevalent condition with limited treatment options. The role of RNA N6-methyladenosine (m⁶A) modification in the pathogenesis of DMED remains elusive. This study aimed to investigate the underlying m⁶A modification patterns and identify potential therapeutic targets for DMED.

A rat model of DMED was established using streptozotocin injection and confirmed by apomorphine-induced penile erection. Erectile function was assessed via cavernous nerve electrostimulation. Fibrosis in the corpus cavernosum was evaluated using Masson's trichrome staining. RNA m⁶A modification levels and the expression of associated methyltransferases were examined by dot blot and quantitative real-time PCR. MeRIP-seq and RNA-seq were employed to identify differentially methylated and expressed genes. Conjoint analysis was performed to explore associated biological processes and identify key genes, which were subsequently validated.

Elevated levels of RNA m⁶A modification were observed in DMED, accompanied by altered expression of METTL14 and METTL3. A total of 2,789 genes associated with 3574 m⁶A peaks were identified (p<0.05). Differentially methylated m⁶A genes were implicated in muscle cell differentiation, cell junction organization, and Wnt signaling pathways. Combined analysis of MeRIP-seq and RNA-seq identified and validated POSTN and LOX as key genes. These genes were associated with fibrosis, cell-matrix adhesion, and regulated Notch signaling pathway, and were predominantly enriched in corpus cavernosum fibroblasts of DMED.

This exploratory study provides the first exploration of RNA m⁶A modification in DMED, and offers novel insights into the pathogenesis of DMED and potential therapeutic targets.