1. Histone Deacetylases 1 and 2 Regulate Microglia Function during Development, Homeostasis, and Neurodegeneration in a Context-Dependent Manner
- Author
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Thomas Blank, Marco Prinz, Melanie Meyer-Luehmann, Mario Kreutzfeldt, Moumita Datta, Patrick Matthias, Stephanie Ziegler-Waldkirch, Tuan Leng Tay, Ori Staszewski, Maximilian Frosch, Elena Raschi, Doron Merkler, and Nora Hagemeyer
- Subjects
0301 basic medicine ,animal structures ,Neurogenesis ,Immunology ,Central nervous system ,Spatial Learning ,Gene Expression ,Histone Deacetylase 2 ,Apoptosis ,Histone Deacetylase 1 ,Mice, Transgenic ,Plaque, Amyloid ,Context (language use) ,ddc:616.07 ,Epigenesis, Genetic ,Histones ,Mice ,03 medical and health sciences ,Phagocytosis ,medicine ,Animals ,Homeostasis ,Immunology and Allergy ,Epigenetics ,Cell Proliferation ,Mice, Knockout ,Memory Disorders ,biology ,Microglia ,Histone deacetylase 2 ,Gene Expression Profiling ,Neurodegeneration ,Neurodegenerative Diseases ,medicine.disease ,HDAC1 ,Cell biology ,Disease Models, Animal ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Histone ,Gene Expression Regulation ,embryonic structures ,biology.protein ,Transcriptome - Abstract
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.
- Published
- 2018