Intermittent myopic visual exposure triggers myopia progression via H3K27me3.

Area of Science:

• Ophthalmology
• Epigenetics
• Molecular Biology

Background:

• Myopia is a global epidemic causing visual impairment, linked to environmental factors like near-work that induce scleral hypoxia.
• The precise molecular pathways translating transient stimuli into sustained myopia progression remain unclear.
• This study investigates how intermittent myopiagenic exposures induce lasting pathological changes in the sclera.

Purpose of the Study:

• To identify epigenetic factors mediating myopia development.
• To elucidate the molecular mechanism linking environmental exposures to myopia progression.
• To investigate the role of H3K27me3 in scleral remodeling and myopia.

Main Methods:

• Integrated human genetic data (MAGIC, UK Biobank) with animal models (mouse, guinea pig FDM).
• Utilized intermittent form-deprivation (iFD) protocols and AAV8-mediated gene manipulation.
• Employed molecular techniques including CUT&Tag, RNA-seq, primary human scleral fibroblast cultures, and protein interaction assays.

Main Results:

• Human myopia genetics showed enrichment of H3K27me3 regulators at myopia-associated loci.
• Increased scleral H3K27me3 and decreased KDM6A/KDM6B demethylases were observed in myopia models.
• Scleral H3K27me3 accumulation, driven by hypoxia-induced USP16/NEDD4 changes, was necessary for myopia development and repressed Sp1, reducing collagen content.

Conclusions:

• Scleral H3K27me3 acts as an epigenetic mediator connecting intermittent exposures to myopia progression.
• The KDM6A-H3K27me3-Sp1 axis provides a molecular framework for understanding myopia development.
• Targeting this axis may offer new therapeutic strategies for myopia control.