TGF-ß1-induced m6A modifications accelerate onset of nuclear cataract in high myopia by influencing the PCP pathway [meRIP-seq]
High myopia is a major cause of blindness worldwide, characterized by early-onset nuclear cataracts, whose underlying mechanisms remains largely unexplained. Here, we identify a conspicuously polarized lens fiber alignment in highly myopic cataracts (HMC) and a simultaneous rise in N6-methyladenosine (m6A) modifications induced by elevated transforming growth factor-ß1 (TGF-ß1) in lens. Mechanistically, methyltransferase METTL3 and m6A reader insulin-like growth factor 2 mRNA binding protein 3 synergistically enhance planar cell polarity (PCP) signaling through affecting mRNA stability of dishevelled 2. This, in turn, alters proliferation, migration, and polarity formation of lens epithelial cells. Moreover, Mettl3 conditional knockout in mice leads to disrupted lens fiber arrangement and alleviates TGF-ß1-induced increase of lens nuclear density. Collectively, these findings highlight the significance of m6A-modified PCP pathway in regulating postnatal lens fiber organization, which may hold great promise as a therapeutic target for HMC. Overall design: RNA profile from human lens capsule tissues from age-related cataract (ARC) and highly myopic cataract (HMC) patients. Expression profiling by high throughput sequencing. Methylation profiling by high throughput sequencing