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

Immunity. 2018 Mar 20;48(3):514-529.e6. doi: 10.1016/j.immuni.2018.02.016. Epub 2018 Mar 13.


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.

Keywords: Alzheimer’s disease; HDACs; epigenetics; microglia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Proliferation
  • Disease Models, Animal
  • Epigenesis, Genetic
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Histone Deacetylase 1 / genetics*
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase 2 / genetics*
  • Histone Deacetylase 2 / metabolism
  • Histones / metabolism
  • Homeostasis*
  • Memory Disorders / genetics
  • Memory Disorders / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microglia / immunology*
  • Microglia / metabolism*
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neurodegenerative Diseases / psychology
  • Neurogenesis / genetics*
  • Neurogenesis / immunology
  • Phagocytosis / immunology
  • Plaque, Amyloid / genetics
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Spatial Learning
  • Transcriptome


  • Histones
  • Histone Deacetylase 1
  • Histone Deacetylase 2