Epigenetics of glaucoma in the trabecular meshwork

Area of Science:

• Ophthalmology and Molecular Biology
• Focuses on the molecular mechanisms underlying glaucoma pathogenesis.

Background:

• Glaucoma is a leading cause of irreversible blindness globally, characterized by elevated intraocular pressure (IOP) and retinal ganglion cell loss.
• Trabecular meshwork (TM) dysfunction is central to glaucoma, regulating aqueous humor outflow and IOP.
• Emerging evidence implicates epigenetic mechanisms, influenced by environmental factors, in TM dysfunction.

Purpose of the Study:

• To review and synthesize current understanding of epigenetic mechanisms in glaucomatous TM remodeling.
• To elucidate the role of specific epigenetic modifications in TM fibrosis and dysfunction.
• To explore novel therapeutic strategies targeting epigenetic pathways in glaucoma.

Main Methods:

• Comprehensive review of existing literature on epigenetic mechanisms in glaucoma.
• Analysis of DNA methylation, histone modifications, non-coding RNAs (ncRNAs), and m⁶A methylation in TM.
• Examination of signaling pathways (e.g., TGF-β, Wnt, RhoA) influenced by epigenetic alterations.

Main Results:

• Aberrant DNA methylation impacts profibrotic and elasticity genes, leading to ECM accumulation and increased outflow resistance.
• Dysregulated miRNA-lncRNA networks and histone modifications affect key signaling pathways involved in TM fibrosis and cellular senescence.
• Emerging roles of m⁶A regulators are identified at the intersection of outflow pathway fibrosis and RGC vulnerability.

Conclusions:

• Epigenetic modifications converge to create a stereotypical glaucomatous TM phenotype.
• Epigenetic modifiers, ncRNA-based therapies, and epigenetic reprogramming present promising TM-targeted and neuroprotective strategies.
• These findings offer novel opportunities for mechanism-based diagnosis and therapeutic intervention in glaucoma.