Epigenetic regulation of brain region-specific microglia clearance activity

Pinar Ayata; Ana Badimon; Hayley J. Strasburger; Mary Kaye Duff; Sarah E. Montgomery; Yong Hwee E. Loh; Anja Ebert; Anna A. Pimenova; Brianna R. Ramirez; Andrew T. Chan; Josefa M. Sullivan; Immanuel Purushothaman; Joseph R. Scarpa; Alison M. Goate; Meinrad Busslinger; Li Shen; Bojan Losic; Anne Schaefer

doi:10.1038/s41593-018-0192-3

Epigenetic regulation of brain region-specific microglia clearance activity

Pinar Ayata, Ana Badimon, Hayley J. Strasburger, Mary Kaye Duff, Sarah E. Montgomery, Yong Hwee E. Loh, Anja Ebert, Anna A. Pimenova, Brianna R. Ramirez, Andrew T. Chan, Josefa M. Sullivan, Immanuel Purushothaman, Joseph R. Scarpa, Alison M. Goate, Meinrad Busslinger, Li Shen, Bojan Losic, Anne Schaefer

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287 Scopus citations

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.

Original language	English
Pages (from-to)	1049-1060
Number of pages	12
Journal	Nature Neuroscience
Volume	21
Issue number	8
DOIs	https://doi.org/10.1038/s41593-018-0192-3
State	Published - 1 Aug 2018

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Ayata, P., Badimon, A., Strasburger, H. J., Duff, M. K., Montgomery, S. E., Loh, Y. H. E., Ebert, A., Pimenova, A. A., Ramirez, B. R., Chan, A. T., Sullivan, J. M., Purushothaman, I., Scarpa, J. R., Goate, A. M., Busslinger, M., Shen, L., Losic, B., & Schaefer, A. (2018). Epigenetic regulation of brain region-specific microglia clearance activity. Nature Neuroscience, 21(8), 1049-1060. https://doi.org/10.1038/s41593-018-0192-3

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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 = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

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day = "1",

doi = "10.1038/s41593-018-0192-3",

language = "English",

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Ayata, P, Badimon, A, Strasburger, HJ, Duff, MK, Montgomery, SE, Loh, YHE, Ebert, A, Pimenova, AA, Ramirez, BR, Chan, AT, Sullivan, JM, Purushothaman, I, Scarpa, JR, Goate, AM, Busslinger, M, Shen, L, Losic, B & Schaefer, A 2018, 'Epigenetic regulation of brain region-specific microglia clearance activity', Nature Neuroscience, vol. 21, no. 8, pp. 1049-1060. https://doi.org/10.1038/s41593-018-0192-3

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T1 - Epigenetic regulation of brain region-specific microglia clearance activity

AU - Ayata, Pinar

AU - Badimon, Ana

AU - Strasburger, Hayley J.

AU - Duff, Mary Kaye

AU - Montgomery, Sarah E.

AU - Loh, Yong Hwee E.

AU - Ebert, Anja

AU - Pimenova, Anna A.

AU - Ramirez, Brianna R.

AU - Chan, Andrew T.

AU - Sullivan, Josefa M.

AU - Purushothaman, Immanuel

AU - Scarpa, Joseph R.

AU - Goate, Alison M.

AU - Busslinger, Meinrad

AU - Shen, Li

AU - Losic, Bojan

AU - Schaefer, Anne

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

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JO - Nature Neuroscience

JF - Nature Neuroscience

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Epigenetic regulation of brain region-specific microglia clearance activity

Abstract

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