Epigenetic control of brain region-specific microglia clearance activity by PRC2
Pinar Ayata1,2, Ana Badimon1, Hayley J. Strasburger1, Mary K. Duff1, Sarah Montgomery1, Yong-Hwee E. Loh1, Anja Ebert3, Anna A. Pimenova1,2, Brianna R. Ramirez1, Andrew T. Chan1, Josefa M. Sullivan1, Immanuel Purushothaman1, Joseph R. Scarpa4, Alison M. Goate1,2,4, Meinrad Busslinger3, Li Shen1, Bojan Losic4, and Anne Schaefer1,2*
1Fishberg Department of Neuroscience, Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; 2Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 3Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria; 4Department of Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Efficient clearance of dying neurons and non-functional synapses, which is carried out by microglia in the brain, is crucial for brain homeostasis and integrity. To avoid a potential damage of microglia on functional neurons, the microglial clearance activity must be tightly regulated and proportional to the degree of neuronal death. Here we show that microglia clearance activity in the adult brain is controlled in a region-specific fashion with highest levels in the cerebellum, where it correlates with ongoing neuronal attrition. We also found that exposure of microglia to early apoptotic cells activates gene expression programs that support clearance function. We provide evidence that clearance activity of striatal and cortical microglia is restricted by epigenetic mechanisms that involve Polycomb Repressive Complex 2 (PRC2). The loss of PRC2 leads to aberrant activation of the microglia clearance phenotype followed by changes in neuron morphology and associated behaviors. Our findings suggest the instructed nature of microglia clearance activity and point to the potential role of epigenetic mechanisms in prevention of microglia-induced neuronal changes associated with neurodegenerative and psychiatric diseases.