Hwang William W, Salinas Ryan D, Siu Jason J, Kelley Kevin W, Delgado Ryan N, Paredes Mercedes F, Alvarez-Buylla Arturo, Oldham Michael C, Lim Daniel A
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.
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.
Elife. 2014 May 27;3:e02439. doi: 10.7554/eLife.02439.
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.
使特化的星形胶质细胞在成年期始终保持神经发生能力的表观遗传机制仍未得到充分了解。在此我们表明，在成年小鼠脑室下区（SVZ）充当神经干细胞（NSC）的星形胶质细胞表达组蛋白甲基转移酶EZH2。这种多梳抑制因子对于神经发生是必需的，与其在SVZ神经干细胞增殖中的作用无关，因为在Ezh2缺失的SVZ神经干细胞中Ink4a/Arf缺陷可挽救细胞增殖，但神经发生仍然存在缺陷。Olig2是EZH2的直接靶点，抑制这种bHLH转录因子对于神经元分化至关重要。此外，Ezh2可防止与非SVZ神经元亚型相关的基因被不适当激活。在人类大脑中，包括局部星形胶质细胞在内的SVZ细胞也表达EZH2，这与出生后神经发生相关。因此，EZH2是一种表观遗传调节因子，可区分具有神经发生能力的SVZ星形胶质细胞，协调成年干细胞生物学中不同且可分离的方面，这对再生医学和肿瘤发生具有重要意义。DOI: http://dx.doi.org/10.7554/eLife.02439.001 。
