title: Distinct and separable roles for EZH2 in neurogenic astroglia.
abstract: The epigenetic mechanisms that enable specialized astrocytes to retain neurogenic competence throughout adult life are still poorly understood. Here we show that astrocytes that serve as neural stem cells (NSCs) in the adult mouse subventricular zone (SVZ) express the histone methyltransferase EZH2. This Polycomb repressive factor is required for neurogenesis independent of its role in SVZ NSC proliferation, as Ink4a/Arf-deficiency in Ezh2-deleted SVZ NSCs rescues cell proliferation, but neurogenesis remains defective. Olig2 is a direct target of EZH2, and repression of this bHLH transcription factor is critical for neuronal differentiation. Furthermore, Ezh2 prevents the inappropriate activation of genes associated with non-SVZ neuronal subtypes. In the human brain, SVZ cells including local astroglia also express EZH2, correlating with postnatal neurogenesis. Thus, EZH2 is an epigenetic regulator that distinguishes neurogenic SVZ astrocytes, orchestrating distinct and separable aspects of adult stem cell biology, which has important implications for regenerative medicine and oncogenesis.DOI: http://dx.doi.org/10.7554/eLife.02439.001.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, USA Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Hwang
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Salinas
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, USA Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Siu
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, USA Department of Pediatrics, University of California, San Francisco, San Francisco, United States.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Kelley
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, USA.
authors.forename: Ryan N
authors.initials: RN
authors.lastname: Delgado
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, USA Department of Neurology, University of California, San Francisco, San Francisco, United States.
authors.forename: Mercedes F
authors.initials: MF
authors.lastname: Paredes
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Alvarez-Buylla
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, USA Department of Neurology, University of California, San Francisco, San Francisco, United States.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Oldham
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, USA Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, USA limd@neurosurg.ucsf.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lim
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; C498409:EZH2 protein, human; C498410:Ezh2 protein, mouse
keywords: EZH2; OLIG2; Polycomb; SVZ neurogenesis; astrocyte heterogeneity; glioma