Epigenetic regulation of brain region-specific microglia clearance activity

Abstract

The rapid elimination of dying neurons and nonfunctional synapses in the brain is carried out by microglia, the resident myeloid cells of the brain. Here we show that microglia clearance activity in the adult brain is regionally regulated and depends on the rate of neuronal attrition. Cerebellar, but not striatal or cortical, microglia exhibited high levels of basal clearance activity, which correlated with an elevated degree of cerebellar neuronal attrition. Exposing forebrain microglia to apoptotic cells activated gene-expression programs supporting clearance activity. We provide evidence that the polycomb repressive complex 2 (PRC2) epigenetically restricts the expression of genes that support clearance activity in striatal and cortical microglia. Loss of PRC2 leads to aberrant activation of a microglia clearance phenotype, which triggers changes in neuronal morphology and behavior. Our data highlight a key role of epigenetic mechanisms in preventing microglia-induced neuronal alterations that are frequently associated with neurodegenerative and psychiatric diseases.

Microglia and sexual differentiation of the developing brain: A focus on ontogeny and intrinsic factors

“…Brain regions are often defined by the primary neuronal subtype contained within that region, as well as to which other regions these neurons connect. However, recent scRNA‐seq and proteomics studies have observed a high level of heterogeneity within individual brain regions (Tasic et al, ; Zeisel et al, ), indicating that in addition to heterogeneity between traditionally defined brain regions, there may also be significant intra‐regional heterogeneity (Ayata et al, ; Silvin & Ginhoux, ). Early flow cytometry‐based studies examining the potential for spatial heterogeneity of microglial phenotypes described marked variations of canonical microglial markers from microglia isolated from the hippocampus, spinal cord, cerebellum, cerebral cortex, and striatum of 11–12 week‐old male mice (de Haas, Boddeke, & Biber, ).…”

Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors

“…Microglia function and phenotype differ by brain region across time and are largely determined by their local environment (Table ; Ayata et al, ; Böttcher et al, ; De Biase et al, ; Doorn et al, ; Grabert et al, ; Masuda et al, ; O'Koren et al, ; Stowell et al, ). During early development, microglia may promote neural proliferation and cell survival by secreting pro‐proliferative cytokines (Antony, Paquin, Nutt, Kaplan, & Miller, ; Arnó et al, ; Morgan, Taylor, & Pocock, ; Shigemoto‐Mogami et al, ; Ueno et al, ), while later they may prune superfluous cells by inducing apoptosis and targeted phagocytosis (Ashwell, ; Cunningham et al, ; Ferrer, Bernet, Soriano, del Rio, & Fonseca, ; Marín‐Teva et al, ; Sierra et al, ; VanRyzin et al, ; Wakselman et al, ).…”

“…Microglia‐specific deletion of the histone deacetylases HDAC1 and 2 prior to birth impairs microglia development, reduces cell number, and induces lasting alterations in adult microglia morphology (Datta et al, ). Moreover, heterogeneity in adult microglia function is driven by signals from the microenvironment and maintained by epigenetic regulation (Ayata et al, ).…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…Indeed, genome‐wide transcriptional studies have reported that the bio‐energetic and immunoregulatory functions of microglia varied considerably in different anatomical regions, evidenced by cerebellar and cortical microglia displaying distinct gene expression profiles under steady‐state conditions (Grabert et al, ). More specifically, a recent study provides convincing evidence of an epigenetic mechanism involved in the clearance activity of microglia that differs regionally in the adult brain (Ayata et al, ). Variations in microglial profiles may also depend on the specific diseases states (Mastroeni et al, ), significantly altered transcripts having been reported in the hippocampus of Alzheimer's disease (AD) and in the substantia nigra of Parkinson's disease (PD), respectively (Mastroeni et al, ).…”