Intermittent myopic visual exposure triggers myopia progression via H3K27me3

Background: Myopia is a global epidemic and a leading cause of visual impairment. It is driven by intermittent environmental exposures, such as near-work, which induce scleral hypoxia. However, the molecular mechanism that translates these transient stimuli into sustained myopia progression remains elusive. We hypothesized that intermittent myopiagenic exposures establish stable pathological changes in the sclera that contribute to myopia development. Methods: We integrated human genetic data from the Myopia Associated Genetics and Intervention Consortium (MAGIC) cohort and the UK Biobank to identify epigenetic factors associated with myopia. Findings were validated in mouse and guinea pig form-deprivation myopia (FDM) models. Intermittent form-deprivation (iFD) protocols were established to investigate how specific epigenetic modifications sustain persistent chromatin remodeling and drive myopia progression. Mechanistic investigations employed Adeno-associated virus serotype 8 (AAV8)-mediated gene knockdown or overexpression, CUT&Tag, RNA-seq, primary human scleral fibroblasts (HSFs) cultures, and protein interaction assays (co-immunoprecipitation and proximity ligation assays). Results: Human myopia genetics reveals significant enrichment of H3K27me3 regulators and targets within myopia-associated loci. FDM models in mice and guinea pigs exhibit an increase in H3K27me3 level and declines in the protein levels of its specific demethylases, KDM6A and KDM6B, in the sclera. Using complementary “intermittent recovery-based inhibition of myopiagenesis” and “intermittent myopiagenic stimulus-induced myopia” models, we demonstrated that increasing the scleral content of H3K27me3, but not of hypoxia-inducible factor-1α (HIF-1α), is necessary for myopiagenesis. Mechanistically, hypoxia decreases deubiquitinase USP16 content while increasing E3 ligase NEDD4 content, leading to the proteasomal degradation of KDM6A and subsequent H3K27me3 accumulation. Gain or loss of scleral H3K27me3 function, respectively induced or suppressed collagen loss and myopia development. Furthermore, H3K27me3 repressed Sp1 transcription, decreasing scleral collagen content and enabling myopia development. Conclusions: Our findings suggested that scleral H3K27me3 is an epigenetic mediator that connects intermittent myopiagenic exposures to persistent chromatin remodeling and myopia progression. The data support a model involving the " KDM6A-H3K27me3-Sp1” axis, providing a molecular framework for understanding the cumulative biological effects of myopiagenic risk factors.