Distinct and separable roles for EZH2 in neurogenic astroglia.
Distinct and separable roles for EZH2 in neurogenic astroglia.
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作者：
Hwang WW;Salinas RD;Siu JJ;Kelley KW;Delgado RN;Paredes MF;Alvarez-Buylla A;Oldham MC;Lim DA
使特化星形胶质细胞在整个成年生活中保持神经源性能力的表观遗传学机制仍然知之甚少。在这里，我们展示了作为神经干细胞(NSCs)的星形胶质细胞在成年小鼠室下区(SVZ)中表达组蛋白甲基转移酶EZH2。这种多梳抑制因子是神经发生所必需的，与其在SVZ NSC增殖中的作用无关，因为在Ezh2缺失的SVZ NSCs中，Ink4a/Arf缺陷可以挽救细胞增殖，但神经发生仍然存在缺陷。OLIG2是EZH2的直接靶标，抑制该转录因子对神经元的分化至关重要。此外，Ezh2阻止与非SVZ神经元亚型相关的基因的不适当激活。在人脑中，包括局部星形胶质细胞在内的SVZ细胞也表达EZH2，与出生后的神经发生相关。因此，EZH2是一种表观遗传调节因子，它区分神经源性SVZ星形胶质细胞，协调成体干细胞生物学的不同和可分离的方面，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除了被称为神经元的数十亿个神经细胞外，大脑和脊髓还含有被称为星形细胞的星形细胞。起初，人们认为所有的星形胶质细胞都是一样的，但后来人们清楚地发现，有几种不同类型的星形胶质细胞执行不同的功能。大多数神经元是在胚胎中形成的，但在大脑深处发现的一些星形胶质细胞可以充当神经性干细胞，并在成年后继续产生新的神经元。然而，目前尚不清楚这些神经源性星形胶质细胞与其他星形胶质细胞的不同之处。现在，Hwang等人。发现神经源性星形胶质细胞含有一种名为EZH2的蛋白质，这是成人大脑中其他类型的星形胶质细胞所没有的。研究人员已经知道，这种蛋白质对大脑发育非常重要，它有助于将DNA紧密包装在细胞核内，并保持基因关闭。众所周知，EZH2还可以防止干细胞过早转变为特殊类型的细胞。但是，令人惊讶的是，Hwang等人。研究发现，EZH2在神经源性星形胶质细胞中有两个不同的作用：它允许它们繁殖，制造更多的星形胶质细胞，它也有助于引导星形胶质细胞成为神经元。Hwang等人。表明不同的基因集合参与了这两个角色。DOI：http://dx.doi.org/10.7554/eLife.02439.002
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 In addition to the billions of nerve cells called neurons, the brain and spinal cord also contain star-shaped cells called astrocytes. At first it was thought that all astrocytes were the same, but it later became clear that there are several different types of astrocytes that perform different functions. Most neurons are formed in the embryo, but some astrocytes that are found deep within the brain can act as ‘neurogenic stem cells’ and continue to produce new neurons during adult life. However, it was not clear how these neurogenic astrocytes were different from other astrocytes. Now Hwang et al. have found that neurogenic astrocytes contain a protein called EZH2 that is not found in other types of astrocyte in the adult brain. Researchers already knew that this protein, which acts to help keep DNA tightly packed inside the nucleus and to keep genes switched off, was important for brain development. EZH2 was also known to prevent stem cells from prematurely turning into specialized cell types. But, surprisingly, Hwang et al. found that EZH2 has two distinct roles in neurogenic astrocytes: it allows them to multiply to make more astrocytes, and it also helps guide astrocytes into becoming neurons. Hwang et al. showed that different sets of genes were involved in these two roles. DOI: http://dx.doi.org/10.7554/eLife.02439.002