title: Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration.
abstract: Normal brain function depends on the interaction between highly specialized neurons that operate within anatomically and functionally distinct brain regions. Neuronal specification is driven by transcriptional programs that are established during early neuronal development and remain in place in the adult brain. The fidelity of neuronal specification depends on the robustness of the transcriptional program that supports the neuron type-specific gene expression patterns. Here we show that polycomb repressive complex 2 (PRC2), which supports neuron specification during differentiation, contributes to the suppression of a transcriptional program that is detrimental to adult neuron function and survival. We show that PRC2 deficiency in striatal neurons leads to the de-repression of selected, predominantly bivalent PRC2 target genes that are dominated by self-regulating transcription factors normally suppressed in these neurons. The transcriptional changes in PRC2-deficient neurons lead to progressive and fatal neurodegeneration in mice. Our results point to a key role of PRC2 in protecting neurons against degeneration.
authors.affiliation: Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: von Schimmelmann
authors.affiliation: Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Feinberg
authors.affiliation: Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Josefa M
authors.initials: JM
authors.lastname: Sullivan
authors.affiliation: Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Ku
authors.affiliation: Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Badimon
authors.affiliation: Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Mary Kaye
authors.initials: MK
authors.lastname: Duff
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|BD2K-LINCS Data Coordination and Integration Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Zichen
authors.identifier: 0000-0002-1415-1286
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|BD2K-LINCS Data Coordination and Integration Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lachmann
authors.affiliation: Genomics Resource Center, The Rockefeller University, New York, New York, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Dewell
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|BD2K-LINCS Data Coordination and Integration Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Avi
authors.initials: A
authors.lastname: Ma'ayan
authors.affiliation: Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
authors.affiliation: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, New York, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tarakhovsky
authors.affiliation: Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Schaefer
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2