@article{583bdf7ae80940afbfaa2f27876a8138,
title = "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.",
author = "Pinar Ayata and Ana Badimon and Strasburger, {Hayley J.} and Duff, {Mary Kaye} and Montgomery, {Sarah E.} and Loh, {Yong Hwee E.} and Anja Ebert and Pimenova, {Anna A.} and Ramirez, {Brianna R.} and Chan, {Andrew T.} and Sullivan, {Josefa M.} and Immanuel Purushothaman and Scarpa, {Joseph R.} and Goate, {Alison M.} and Meinrad Busslinger and Li Shen and Bojan Losic and Anne Schaefer",
note = "Funding Information: We thank D. Littman (NYU School of Medicine, NY) for Cx3cr1CreErt2/+(Litt) mice; N. Heintz (Rockefeller University, NY) for Tg(Prox1-Cre)SJ39 and Tg(Aldh1l1-eGFPL10a) mice; A. Domingos (Instituto Gulbenkian de Ci{\^e}ncia, PT) and J. Friedman (Rockefeller University, NY) for Eef1a1LSL.eGFPL10a/+ mice; G. Lemke (Salk Institute, CA) for brain tissue from Axl−/−Mertk−/− mice; the Flow Cytometry CoRE at Icahn School of Medicine for cytometry assistance; I. Lemischka (Icahn School of Medicine, NY) for Fluidigm C1 use; O. Butovsky (Harvard Medical School, MA) for P2RY12 antibody; and J.W. Murray for ImageJ automation. We are very grateful to D. Schafer, E. Marcora, A. Tarakhovsky, J.W. Murray, and all Schaefer lab and Ronald M. Loeb Center members for helpful discussions and comments on the manuscript. This work was supported by the National Institutes of Health (NIH) Director New Innovator Award DP2 MH100012-01 (A.S.), R01NS091574 (A.S.), R21 MH115353 (A.S.), 1 RF1 AG054011-01 (A.M.G. and A.S.), JPB Foundation (A.M.G.), NARSAD Young Investigator Award #25065 (P.A.), Boehringer Ingelheim and the Austrian Industrial Research Promotion Agency FFG-852936 (M.B.), T32AG049688 (A.B.), F30MH106293 (J.R.S), and Ruth L. Kirschstein NRSA fellowship F31MH111147 (J.M.S). Publisher Copyright: {\textcopyright} 2018, The Author(s).",
year = "2018",
month = aug,
day = "1",
doi = "10.1038/s41593-018-0192-3",
language = "English",
volume = "21",
pages = "1049--1060",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "8",
}