Methylome profiling reveals epigenetic alterations in the trabecular meshwork of primary open-angle glaucoma

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide. While aberrant DNA methylation may contribute, a genome-wide profile in trabecular meshwork (TM) is lacking. This study performed reduced-representation bisulfite sequencing (RRBS) on TM samples from 42 POAG patients and 20 non-glaucomatous controls, identifying 8885 significant differentially methylated CpG sites (DMCs) and 3148 differentially methylated regions (DMRs), revealing a pronounced hypomethylation pattern in POAG. Hypomethylated genes were associated with ossification, collagen fibril organization, and the RhoA/ROCK signaling, whereas hypermethylated genes were enriched in androgen receptor signaling, the NABA core matrisome, and actin filament processes-collectively highlighting extracellular matrix (ECM) dysregulation as a central theme. Integrated methylome-transcriptome analysis identified four high-priority genes (COL5A1, COL5A2, JAM3, and HTRA1) among hypomethylated-upregulated candidates, implicating them in pathogenic ECM remodeling in POAG. This study presents the first RRBS-based methylome profile of POAG, revealing significant epigenetic alterations in pathways and genes related to TM dysfunction. These findings enhance our understanding of the molecular mechanisms underlying POAG and may inform future therapeutic strategies.