Astrocyte epigenetics in development, aging, and neurodegeneration: a DNA methylation perspective

Epigenetic modifications, including DNA methylation, have long been associated with developmental programming, as well as aging and disease states. However, our understanding of cell-specific epigenomic landscapes remains limited, especially in the context of brain aging and neurodegeneration. In cases of late-onset brain disorders, such as Alzheimer's disease, progressive supranuclear palsy, Parkinson's disease, and frontotemporal dementia, unraveling cell-specific epigenomic contributions is particularly necessary to better understand the molecular contributors to early disease states, which may help enhance diagnostic and therapeutic measures. While whole brain tissue and neuronal cell-type-specific methylomic contributions have been extensively studied, those of glia, including astrocytes, remain poorly elucidated. Given the key role of DNA methylation in guiding neurodevelopmental timing and gliogenic onset, it is likely that these modifications alter astrocyte functionality with age and disease. Here, we briefly review astrocyte development in the context of DNA methylation and highlight key instances where methylomic changes contribute to astrocyte maturation and functionality. We also point to evidence showing extensive transcriptomic and functional changes associated with aged and diseased astrocytes and explore the relevance of DNA methylation in these conditions. Ultimately, elucidating molecular drivers of disease states in astrocytes will allow for a better understanding of cell-specific contributions and pave the way for future research directed at cell-specific therapeutics.