Genome-wide methylation analysis unveils genes and pathways with altered methylation profiles in pterygium

Abstract

Pterygium is a highly prevalent ocular surface disease, particularly in equatorial regions, with no pharmaceutical intervention available and surgical excision remaining the only treatment option. Ultraviolet (UV) radiation from sunlight is widely recognized as the primary cause of pterygium. While chronic UV exposure induces epigenetic changes in the skin contributing to skin cancer, comprehensive studies on epigenetic alterations in pterygium remain unpublished, and causal relationships have yet to be established. This study aimed to investigate genome-wide methylation changes in pterygium using the Illumina Infinium Epic v2.0 Methylation array. We identified 1052 hypermethylated CpGs (499 genes) and 687 hypomethylated CpGs (340 genes) in pterygium tissue compared to control conjunctival tissue from patients undergoing cataract surgery (Δβ>|0.1|, P < 0.05). Hypomethylated genes were mainly associated with PI3K-Akt and MAPK pathways, while hypermethylated genes were enriched in pathways related to oxidative stress, autophagy, DNA repair, and Wnt signaling inhibition. Comparing these findings with transcriptomic datasets revealed 28 hypermethylated genes with downregulated transcripts and 74 hypomethylated genes with upregulated transcripts. qPCR validation confirmed upregulation of hypomethylated genes (MMP2, FBLN5, ZEB1) and downregulation of hypermethylated genes (SAMSN1, CBX4) at the transcript level. These findings suggest that dysregulated DNA methylation may contribute to pterygium pathogenesis by upregulating genes involved in cell proliferation, survival, angiogenesis, fibrosis, and extracellular matrix remodeling, while silencing genes associated with oxidative stress response, autophagy, and DNA damage repair. These insights into the global methylation landscape of pterygium open avenues for detailed functional analysis, potentially guiding targeted therapeutic strategies.