Histone Deacetylases 1 and 2 Regulate Microglia Function during Development, Homeostasis, and Neurodegeneration in a Context-Dependent Manner

Publication date: Available online 13 March 2018
Source:Immunity
Author(s): Moumita Datta, Ori Staszewski, Elena Raschi, Maximilian Frosch, Nora Hagemeyer, Tuan Leng Tay, Thomas Blank, Mario Kreutzfeldt, Doron Merkler, Stephanie Ziegler-Waldkirch, Patrick Matthias, Melanie Meyer-Luehmann, Marco Prinz
Microglia as tissue macrophages contribute to the defense and maintenance of central nervous system (CNS) homeostasis. Little is known about the epigenetic signals controlling microglia function in vivo. We employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases, Hdac1 and Hdac2. Prenatal ablation of Hdac1 and Hdac2 impaired microglial development. Mechanistically, the promoters of pro-apoptotic and cell cycle genes were hyperacetylated in absence of Hdac1 and Hdac2, leading to increased apoptosis and reduced survival. In contrast, Hdac1 and Hdac2 were not required for adult microglia survival during homeostasis. In a mouse model of Alzheimer's disease, deletion of Hdac1 and Hdac2 in microglia, but not in neuroectodermal cells, resulted in a decrease in amyloid load and improved cognitive impairment by enhancing microglial amyloid phagocytosis. Collectively, we report a role for epigenetic factors that differentially affect microglia development, homeostasis, and disease that could potentially be utilized therapeutically.

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Teaser

Little is known about the epigenetic signals that control microglia function in vivo. Datta et al. show that histone deacetylases Hdac1 and Hdac2 are essential for microglial survival and expansion during development but not during steady state. In Alzheimer's disease mouse model, deletion of microglial Hdac1 and Hdac2 reduces amyloid pathology and improves cognitive function.


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