Distinct and separable roles for EZH2 in neurogenic astroglia
William W Hwang,
Ryan D Salinas,
Jason J Siu,
Kevin W Kelley,
Ryan N Delgado,
Mercedes F Paredes,
Arturo Alvarez-Buylla,
Michael C Oldham,
Daniel A Lim
Affiliations
William W Hwang
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
Ryan D Salinas
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
Jason J Siu
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
Kevin W Kelley
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
Ryan N Delgado
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
Mercedes F Paredes
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
Arturo Alvarez-Buylla
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
Michael C Oldham
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
Daniel A Lim
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
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.
