JNK-dependent gene regulatory circuitry governs mesenchymal fate.
JNK-dependent gene regulatory circuitry governs mesenchymal fate.
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DOI：
10.15252/embj.201490693
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发表时间：
2015-08-13
期刊：
影响因子：
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通讯作者：
Tiwari VK
中科院分区：
文献类型：
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作者：
Sahu SK;Garding A;Tiwari N;Thakurela S;Toedling J;Gebhard S;Ortega F;Schmarowski N;Berninger B;Nitsch R;Schmidt M;Tiwari VK
上皮细胞向间质细胞转化（EMT）是一个细胞失去细胞间接触而变得能动的生物学过程。EMT在发育过程中使用，例如，触发神经嵴迁移和癌症转移。尽管取得了进展，JNK信号转导的动力学，其在全基因组转录重编程中的作用，以及在EMT过程中涉及的下游效应物仍然在很大程度上未知。在这里，我们表明，JNK是不需要的启动，但与EMT相关的表型变化的进展。这种依赖性是由JNK驱动的关键EMT基因的转录重编程引起的，并涉及其染色质状态的变化。此外，我们确定了八个新的JNK诱导的转录因子，需要适当的EMT。这些因子中的三个也在侵袭性癌细胞中高度表达，它们在基因调节中起作用以维持间充质身份。这些因子也在体内神经元发育和神经元迁移中被诱导。这些全面的发现揭示了JNK通路在定义间充质身份基础的转录组中的动力学独特作用，并揭示了在发育和疾病期间介导这些反应的新型转录因子。
The epithelial to mesenchymal transition (EMT) is a biological process in which cells lose cell–cell contacts and become motile. EMT is used during development, for example, in triggering neural crest migration, and in cancer metastasis. Despite progress, the dynamics of JNK signaling, its role in genomewide transcriptional reprogramming, and involved downstream effectors during EMT remain largely unknown. Here, we show that JNK is not required for initiation, but progression of phenotypic changes associated with EMT. Such dependency resulted from JNK-driven transcriptional reprogramming of critical EMT genes and involved changes in their chromatin state. Furthermore, we identified eight novel JNK-induced transcription factors that were required for proper EMT. Three of these factors were also highly expressed in invasive cancer cells where they function in gene regulation to maintain mesenchymal identity. These factors were also induced during neuronal development and function in neuronal migration in vivo. These comprehensive findings uncovered a kinetically distinct role for the JNK pathway in defining the transcriptome that underlies mesenchymal identity and revealed novel transcription factors that mediate these responses during development and disease.