Polycomb Repressive Complex 2 (PRC2): A Context-Dependent Epigenetic Regulator of Brain Aging

Brain aging is characterized by extensive and dynamic epigenetic changes that reshape chromatin architecture and influence gene regulatory networks, leading to deregulation of transcriptional programs essential for neuronal survival, synaptic plasticity, and cognitive function. Emerging studies highlight the pivotal regulatory role of the Polycomb Repressive Complex 2 (PRC2) in brain aging, functioning mainly as an epigenetic silencer through the establishment of the H3K27me3 histone mark at gene promoters and enhancers, leading to transcriptional repression. Altered distribution and decreased activity of PRC2 during aging disrupts the balance between gene activation and repression, affecting pathways involved in neurogenesis, synaptic plasticity and stress response. Further interplay with other epigenetic regulators such as histone deacetylase 2 (HDAC2), DNA methyltransferases and non-coding RNAs forms an extensive network that contributes to cognitive decline, increasing vulnerability for neurodegeneration. In this review, we describe structural and functional aspects of PRC2, with emphasis on the potential of this epigenetic context-dependent regulator to integrate developmental, environmental and aging-related signals, to shape the transcriptional landscape of aging brain. We also discuss the newly developed PRC2-AgeIndex, which serves as a prognostic biomarker for age-related neurodegeneration and monitoring treatment response, as well as current PRC2-targeting options for healthy brain aging.