Histone modifications and chromatin landscapes in microglial function: Developmental imprinting and disease-associated reprogramming.

Microglia, the brain's resident immune cells, rely on histone modifications and chromatin remodeling to sculpt their identity across the trajectory from development through aging. Recent studies have identified enhancer rewiring and metabolic-epigenetic coupling-exemplified by histone lactylation-as central drivers of microglial plasticity. Disruption of this regulatory balance drives the transition from homeostatic microglia toward disease-associated microglia (DAM) in Alzheimer's and Parkinson's diseases. This Review examines emerging concepts such as trained innate immunity, state-specific enhancer landscapes, and regional heterogeneity, and posits that epigenetic reprogramming is a central mechanism governing microglial functional transitions. These insights reveal promising therapeutic targets; however, a pressing prerequisite for clinical translation is to rigorously establish the causality of these epigenetic changes across diverse model systems, sexes, and brain regions.