HDAC1/2 are required for microglia identity during development, homeostasis and neurodegeneration in a context-dependent manner [ChIP inducible knockout on FAD background]

Microglia as tissue macrophages of the central nervous system (CNS) provide immunological defense and contribute to the establishment and maintenance of CNS homeostasis. Several transcription factors have been described that regulate microglia development and its steady state form, however little is known about the epigenetic signals that control microglia function in vivo. Here, we employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases (HDACs), Hdac1 and 2. Prenatal ablation of Hdac1 and 2 from microglia drastically impaired microglial development with reduced cell number, altered morphology and induction of apoptosis. Comparative transcriptomic profiling revealed an essential role of Hdac1/2 in the regulation of microglia survival and expansion. Mechanistically, hyperacetylation at H3K9 and H3K27 was found at the promoters of pro-apoptotic and cell cycle genes in the absence of Hdac1/2. In contrast, Hdac1/2 were not required in adult microglia during homeostasis. In a mouse model of Alzheimer’s disease, suppression of Hdac1/2 in microglia, but not in neuroectodermal cells, remarkably displayed substantial decrease in amyloid load and improved cognitive impairment by enhancing microglial amyloid phagocytosis. Collectively, we report a previously unknown role of epigenetic factors that differentially affect microglia development, homeostasis and disease that could potentially be utilized therapeutically.