Epigenetic coordination of signaling pathways during the epithelial-mesenchymal transition.
Epigenetic coordination of signaling pathways during the epithelial-mesenchymal transition.
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DOI：
10.1186/1756-8935-6-28
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发表时间：
2013-09-02
影响因子：
3.9
通讯作者：
Bekiranov S
中科院分区：
文献类型：
--
作者：
Cieślik M;Hoang SA;Baranova N;Chodaparambil S;Kumar M;Allison DF;Xu X;Wamsley JJ;Gray L;Jones DR;Mayo MW;Bekiranov S
上皮-间质转化（EMT）是伤口愈合和发展所需的去分化过程。在上皮来源的肿瘤中，EMT的异常诱导有助于癌症进展和转移。研究已经开始暗示EMT中的表观遗传重编程;然而，重编程与细胞过程协调之间的关系在很大程度上尚未探索。我们以前已经开发了一个系统来研究EMT在一个典型的非小细胞肺癌（NSCLC）模型。在这个系统中，我们已经表明，诱导EMT导致组成型NF-κB活性。我们假设染色质重塑在细胞信号通路的持续失调中起作用。我们绘制了16个组蛋白修饰和上皮和间充质状态的两个变体。在基因和增强子位点定量表观遗传变化的组合模式。我们发现了一个独特的染色质签名之间的基因在完善的EMT途径。引人注目的是，这些基因只是差异表达基因中的一小部分。在假定的增强子的基因与'EMT签名'，我们观察到高度协调的表观遗传激活或抑制。此外，被激活的增强子被一组转录因子结合，所述转录因子与结合抑制的增强子的转录因子不同。具有“EMT标记”的上调基因是NF-κB的上游调节因子，但也在其启动子和增强子处被NF-κB结合。这些结果提示染色质介导的正反馈可能是持续NF-κB激活的机制。在EMT的几个关键途径中，基因和增强子存在高度特异性的表观遗传调控。染色质状态的这些变化的位点暗示了在EMT中具有关键作用的几种诱导型转录因子（NF-κB、AP-1和MYC）作为这种重编程的靶点。此外，我们发现的证据表明，这些转录因子是在染色质介导的转录反馈回路，调节关键EMT基因。总之，我们建立了染色质重塑和细胞重编程的变化之间的重要联系。
The epithelial-mesenchymal transition (EMT) is a de-differentiation process required for wound healing and development. In tumors of epithelial origin aberrant induction of EMT contributes to cancer progression and metastasis. Studies have begun to implicate epigenetic reprogramming in EMT; however, the relationship between reprogramming and the coordination of cellular processes is largely unexplored. We have previously developed a system to study EMT in a canonical non-small cell lung cancer (NSCLC) model. In this system we have shown that the induction of EMT results in constitutive NF-κB activity. We hypothesized a role for chromatin remodeling in the sustained deregulation of cellular signaling pathways. We mapped sixteen histone modifications and two variants for epithelial and mesenchymal states. Combinatorial patterns of epigenetic changes were quantified at gene and enhancer loci. We found a distinct chromatin signature among genes in well-established EMT pathways. Strikingly, these genes are only a small minority of those that are differentially expressed. At putative enhancers of genes with the ‘EMT-signature’ we observed highly coordinated epigenetic activation or repression. Furthermore, enhancers that are activated are bound by a set of transcription factors that is distinct from those that bind repressed enhancers. Upregulated genes with the ‘EMT-signature’ are upstream regulators of NF-κB, but are also bound by NF-κB at their promoters and enhancers. These results suggest a chromatin-mediated positive feedback as a likely mechanism for sustained NF-κB activation. There is highly specific epigenetic regulation at genes and enhancers across several pathways critical to EMT. The sites of these changes in chromatin state implicate several inducible transcription factors with critical roles in EMT (NF-κB, AP-1 and MYC) as targets of this reprogramming. Furthermore, we find evidence that suggests that these transcription factors are in chromatin-mediated transcriptional feedback loops that regulate critical EMT genes. In sum, we establish an important link between chromatin remodeling and shifts in cellular reprogramming.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
64.8
作者：
Albert, R;Jeong, H;Barabási, AL
通讯作者：
Barabási, AL
DOI：
10.1088/1742-5468/2008/10/p10008
发表时间：
2008-10-01
影响因子：
2.4
作者：
Blondel, Vincent D.;Guillaume, Jean-Loup;Lefebvre, Etienne
通讯作者：
Lefebvre, Etienne
影响因子：
8
作者：
Chua, H. L.;Bhat-Nakshatri, P.;Nakshatri, H.
通讯作者：
Nakshatri, H.