Epigenetic Regulation of Extracellular Matrix Remodeling in Skin Aging: Mechanisms and Interactions

Abstract

Skin aging results from complex interactions between genetic factors, environmental stressors, and epigenetic modifications that regulate extracellular matrix (ECM) remodeling. Accumulation of senescent cells impairs tissue regeneration through mechanisms including telomere shortening, reactive oxygen species accumulation, and ultraviolet (UV) radiation exposure. While epigenetic pathways regulate skin homeostasis, regeneration, and senescence, the specific epigenetic changes occurring during UV exposure, chronological aging, and neonatal development remain incompletely characterized. This study examined transcriptomic profiles of human skin tissues across developmental stages (neonatal to adult), chronological aging, and various UV exposure conditions using bioinformatic analysis in R (version 4.0.3). Significant epigenetic landscape alterations were identified during skin development, including changes in histone modifications, genomic imprinting, and N6-methyladenosine (m6A) RNA modification. These epigenetic changes primarily affected collagen synthesis, ECM organization, immune function, and keratinization pathways. Key epigenetic effectors regulating ECM architecture included IGF2BP2, GATA2, GATA3, CPA4, and CDK1, while immune function correlated with VEGFA, CDK1, and PRKCB expression. The m6A reader proteins (IGF2BP2, IGF2BP3, HNRNPA2B1, EIF3G) showed strong associations with antigen processing and presentation pathways. UV exposure, even at minimal erythema-inducing doses, altered expression of epigenetic effectors controlling ECM architecture, cell-matrix adhesion, innate immunity, mitochondrial function, and mRNA processing. Notably, UV-induced epigenetic alterations were more pronounced in aged versus young skin. Analysis of progeroid syndrome patient skin revealed molecular signatures resembling naturally aged skin, validating these models for aging research. These findings demonstrate that histone modifications, genomic imprinting, and m6A modifications play essential roles in skin development and aging, with UV exposure accelerating age-related epigenetic changes. This study provides a framework for understanding epigenetic mechanisms underlying skin aging and potential therapeutic targets.