The mRNA Stability of PIEZO1, Regulated by Methyltransferase-Like 3 via N 6 -Methylation of Adenosine Modification in a YT521-B Homology Domain Family 2-Dependent Manner, Facilitates the Progression of Diabetic Retinopathy.

Diabetic retinopathy (DR) is the major ocular complication of diabetes caused by chronic hyperglycemia, which leads to incurable blindness. Currently, the effectiveness of therapeutic interventions is limited. This study aimed to investigate the function of piezo-type mechanosensitive ion channel component 1 (PIEZO1) and its potential regulatory mechanism in DR progression. PIEZO1 expression was up-regulated in the retinal tissues of streptozotocin-induced diabetic mice and high-glucose (HG)-triggered Müller cells. Functionally, the knockdown of PIEZO1 improved the abnormal retinal function of diabetic mice and impeded inflammatory cytokine secretion and gliosis of Müller cells under HG conditions. Mechanistic investigations using RNA immunoprecipitation-real-time quantitative PCR, methylation RNA immunoprecipitation-real-time quantitative PCR, and luciferase reporter assays demonstrated that PIEZO1 was a downstream target of methyltransferase-like 3 (METTL3). METTL3-mediated N ⁶ -methyladenosine (m ⁶ A) modification within the coding sequence of PIEZO1 mRNA significantly shortened its half-life. In HG-stimulated cells, there was a negative regulatory relationship between PIEZO1 and YTH (YT521-B homology) domain family 2 (YTHDF2), a recognized m ⁶ A reader. The loss of YTHDF2 resulted in an extended half-life of PIEZO1 in cells with overexpression of METTL3, indicating that the effect of METTL3 on the mRNA stability of PIEZO1 was dependent on YTHDF2. Taken together, this study demonstrated the protective role of the PIEZO1 silencing in DR development, and that the degradation of PIEZO1 mRNA is accelerated by METTL3/YTHDF2-mediated m ⁶ A modification.
Competing Interests: Disclosure Statement None declared.
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