State-specific enhancer landscapes govern microglial plasticity.

Single-cell transcriptomic studies have identified distinct microglial subpopulations with shared and divergent gene signatures across development, aging, and disease. Whether these microglial subsets represent ontogenically separate lineages of cells or are manifestations of plastic changes in microglial states downstream of some converging signals is unknown. Furthermore, despite the well-established role of enhancer landscapes underlying the identity of microglia, the extent to which histone modifications and DNA methylation regulate microglial state switches at enhancers has not been defined. Here, using genetic fate mapping, we demonstrated the common embryonic origin of proliferative-region-associated microglia enriched in developing white matter and tracked their dynamic transitions into disease-associated microglia and white matter-associated microglia in disease and aging contexts, respectively. This study links spatiotemporally discrete microglial states through their transcriptomic and epigenomic plasticity, while revealing state-specific enhancer histone modifications and transcription regulators that govern state transitions in health and disease.