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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genomic code for Sox10 activation reveals a key regulatory enhancer for cranial neural crest
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Genomic code for Sox10 activation reveals a key regulatory enhancer for cranial neural crest

机译：Sox10激活的基因组代码揭示了颅神经c的关键调控增强剂

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摘要

The neural crest is a multipotent, stem cell-like population that migrates extensively in the embryo and forms a wide array of derivatives, ranging from neurons to melanocytes and cartilage. Analyses of the gene regulatory network driving neural crest development revealed SoxW as one of the earliest neural crest-specifying genes, cell-autonomously driving delamination and directly regulating numerous downstream effectors and differentiation gene batteries. In search of direct inputs to the neural crest specifier module, we dissected the chick SoxW genomic region and isolated two downstream regulatory regions with distinct spatiotemporal activity. A unique element, Sox10E2 represents the earliest-acting neural crest cis-regulatory element, critical for initiating SoxW expression in newly formed cranial, but not vagal and trunk neural crest. A second element, Sox10E1, acts in later migrating vagal and trunk crest cells. Deep characterization of Sox10E2 reveals Sox9, Ets1, and cMyb as direct inputs mediating enhancer activity. ChIP, DNA-pull down, and gel-shift assays demonstrate their direct binding to the Sox10E2 enhancer in vivo, whereas mutation of their corresponding binding sites, or inactivation of the three upstream regulators, abolishes both reporter and endogenous SoxW expression. Using cis-regulatory analysis as a tool, our study makes critical connections within the neural crest gene regulatory network, thus being unique in establishing a direct link of upstream effectors to a key neural crest specifier.
机译：神经c是一种多能干细胞样种群，在胚胎中广泛迁移并形成多种衍生物，范围从神经元到黑素细胞和软骨。对驱动神经c发育的基因调控网络的分析表明，SoxW是最早的神经rest特异性基因之一，细胞自主驱动脱层并直接调控众多下游效应子和分化基因电池。在直接输入神经c说明符模块中，我们解剖了雏鸡的SoxW基因组区域并隔离了两个具有不同时空活动的下游调控区域。 Sox10E2是唯一起作用的元素，它是最早起作用的神经c顺式调节元件，对于启动新形成的颅骨中的SoxW表达至关重要，但对于迷走神经和躯干神经c却不起作用。第二个元素Sox10E1在后来的迷走神经和躯干trunk细胞中起作用。 Sox10E2的深入表征揭示了Sox9，Ets1和cMyb是介导增强子活性的直接输入。 ChIP，DNA下拉和凝胶移位试验证明了它们在体内直接与Sox10E2增强子结合，而其相应结合位点的突变或三个上游调节子的失活则消除了报告基因和内源性SoxW的表达。使用顺式调控分析作为工具，我们的研究在神经regulatory基因调控网络内建立了关键的联系，因此在建立上游效应子与关键神经rest指定者的直接联系方面独树一帜。

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