METTL3-m6A-mediated TGF-β signaling promotes Fuchs endothelial corneal dystrophy via regulating corneal endothelial-to-mesenchymal transition.

Abstract

Fuchs endothelial corneal dystrophy (FECD) is the leading cause of vision-threatening corneal endothelial dystrophy without pharmacologic treatments. Corneal endothelial-mesenchymal transition (cEndMT), a specific cellular phenotypic transition, is implicated in the vicious cycle in FECD pathogenesis. Here, we investigated the reversible epigenetic regulation of N⁶-methyladenosine (m⁶A) during cEndMT process and FECD progression. The m⁶A writer methyltransferase-like 3 (METTL3) was significantly upregulated in FECD models and induced transcriptomic hypermethylation, including TGFB2 mRNA. METTL3 promoted the translation of hypermethylated TGFB2 mRNA in an YTHDF1-dependent manner, resulting in upregulation of TGF-β2 protein and activation of TGF-β signaling. Intervention of METTL3 expression or catalytic activity could suppress TGF-β signaling activation, subsequently ameliorate cEndMT process and FECD progression. This study reveals unique METTL3-m⁶A-mediated mechanism in regulating cEndMT process, suggesting the prevailing role of m⁶A in cellular phenotypic transition. Targeting METTL3/m⁶A is a promising strategy for FECD treatment. Schematic representation of METTL3-m⁶A-TGF-β signaling regulating FCED. In the context of environmental stress, METTL3 is upregulated in corneal endothelium, which in turn leads to increased m⁶A level of TGFB2 mRNA, upregulation of TGF-β2 protein via YTHDF1 mechanism, and activation of TGF-β signaling pathway. The regulation of these mechanisms results in the progressive irreversible transition of corneal endothelial cells from their specific phenotype to a mesenchymal phenotype, which accelerates the progression of FECD.