Geminin regulates the transcriptional and epigenetic status of neuronal fate-promoting genes during mammalian neurogenesis.
Geminin regulates the transcriptional and epigenetic status of neuronal fate-promoting genes during mammalian neurogenesis.
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Geminin 在哺乳动物神经发生过程中调节神经元命运促进基因的转录和表观遗传状态。
DOI：
10.1128/mcb.00737-12
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发表时间：
2012
影响因子：
5.3
通讯作者：
Kroll,KristenL
中科院分区：
文献类型：
--
作者：
Yellajoshyula,Dhananjay;Lim,Jong-won;ThompsonJr,DominicM;Witt,JacobS;Patterson,EthanS;Kroll,KristenL
调节从血统受限的祖细胞到终末分化细胞的转变是神经系统发育的一个中心方面。在此，我们从机制水平上研究了核蛋白Ginin在Xenopus原代神经发生和哺乳动物神经元体外分化过程中的调节作用。后一项工作利用了来自胚胎干细胞的神经细胞和体外培养的胚胎癌细胞以及来自小鼠前脑的神经干细胞。在所有这些背景下，Gminin拮抗神经基础螺旋-环-螺旋(BHLH)转录因子激活促进神经发生的转录程序的能力。此外，双黄素在编码促进神经发生的转录因子的基因上促进了二价染色质状态，其特征是既存在激活的组蛋白修饰，也存在抑制组蛋白修饰。这种表观遗传状态抑制了调控未分化干细胞和神经元前体细胞对神经元谱系承诺的基因的表达。然而，维持高水平的双黄素并不足以阻止终末神经元分化。因此，这些数据支持这样一种模型，即Gminin通过调节表观遗传状态和编码神经发生促进因子的基因的表达来促进神经元前体细胞状态。在哺乳动物神经发生过程中，作用于这些细胞的额外发育信号可以控制它们向终末神经元或神经胶质分化的转变。
Regulating the transition from lineage-restricted progenitors to terminally differentiated cells is a central aspect of nervous system development. Here, we investigated the role of the nucleoprotein geminin in regulating neurogenesis at a mechanistic level during bothXenopusprimary neurogenesis and mammalian neuronal differentiationin vitro. The latter work utilized neural cells derived from embryonic stem and embryonal carcinoma cellsin vitroand neural stem cells from mouse forebrain. In all of these contexts, geminin antagonized the ability of neural basic helix-loop-helix (bHLH) transcription factors to activate transcriptional programs promoting neurogenesis. Furthermore, geminin promoted a bivalent chromatin state, characterized by the presence of both activating and repressive histone modifications, at genes encoding transcription factors that promote neurogenesis. This epigenetic state restrains the expression of genes that regulate commitment of undifferentiated stem and neuronal precursor cells to neuronal lineages. However, maintaining geminin at high levels was not sufficient to prevent terminal neuronal differentiation. Therefore, these data support a model whereby geminin promotes the neuronal precursor cell state by modulating both the epigenetic status and expression of genes encoding neurogenesis-promoting factors. Additional developmental signals acting in these cells can then control their transition toward terminal neuronal or glial differentiation during mammalian neurogenesis.