YAP1 Exerts Its Transcriptional Control via TEAD-Mediated Activation of Enhancers.
YAP1 Exerts Its Transcriptional Control via TEAD-Mediated Activation of Enhancers.
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DOI：
10.1371/journal.pgen.1005465
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发表时间：
2015-08
期刊：
影响因子：
4.5
通讯作者：
Bauer A
中科院分区：
文献类型：
--
作者：
Stein C;Bardet AF;Roma G;Bergling S;Clay I;Ruchti A;Agarinis C;Schmelzle T;Bouwmeester T;Schübeler D;Bauer A
YAP 1是Hippo通路的主要效应子，也是一种公认的癌基因。在几种类型的人类癌症中观察到由于Hippo通路组分突变或YAP 1扩增导致的YAP 1活性升高。在这里，我们研究了它在YAP 1激活的癌细胞以及非转化细胞中的基因组结合景观。我们证明，TEAD转录因子介导的YAP 1染色质结合全基因组，进一步解释其主导作用的主要介质的YAP 1转录活性。此外，我们表明，YAP 1很大程度上发挥其转录控制通过远端增强子，标记H3 K27乙酰化和YAP 1是必要的，这个染色质标记在结合增强子和相关基因的活性。这项工作建立了YAP 1介导的转录调控远端增强子，并提供了一组扩展的靶基因，从而为研究YAP 1在正常和癌症环境中的功能提供了基本来源。YAP 1/Hippo信号通路是器官大小和组织稳态的关键调节因子，其失调与癌症发展有关。YAP 1是一种转录辅激活因子，也是一种公认的癌基因，据报道其活性升高发生在人类癌症中。全面鉴定YAP 1调控基因及其作用模式对于揭示可用于治疗干预的YAP 1生物学具有重要意义。为此，我们进行了全基因组分析，以确定在代表不同YAP 1/Hippo途径肿瘤病因的癌细胞系和非转化成纤维细胞中YAP 1占据的位点。我们的数据表明，YAP 1活性介导的主要是通过TEAD转录因子支持的重要性TEAD作为YAP 1-辅激活因子活性的主要介质。我们进一步表明，YAP 1和TEAD 1发挥其转录控制通过结合增强子，导致特征染色质的变化和远端激活的基因。通过将增强子与基因连接，我们提供了一系列致癌环境中的新型YAP 1靶基因，我们表明这些基因可以很容易地用于肿瘤分类，并为进一步研究提供了基础。
YAP1 is a major effector of the Hippo pathway and a well-established oncogene. Elevated YAP1 activity due to mutations in Hippo pathway components or YAP1 amplification is observed in several types of human cancers. Here we investigated its genomic binding landscape in YAP1-activated cancer cells, as well as in non-transformed cells. We demonstrate that TEAD transcription factors mediate YAP1 chromatin-binding genome-wide, further explaining their dominant role as primary mediators of YAP1-transcriptional activity. Moreover, we show that YAP1 largely exerts its transcriptional control via distal enhancers that are marked by H3K27 acetylation and that YAP1 is necessary for this chromatin mark at bound enhancers and the activity of the associated genes. This work establishes YAP1-mediated transcriptional regulation at distal enhancers and provides an expanded set of target genes resulting in a fundamental source to study YAP1 function in a normal and cancer setting. The YAP1/Hippo signaling pathway is a key regulator of organ size and tissue homeostasis, and its dysregulation is linked to cancer development. Elevated activity of YAP1, a transcriptional coactivator and well-established oncogene has been reported to occur in human cancers. Comprehensive identification of YAP1 regulated genes and its mode of action will be of high importance to uncover YAP1 biology that could be exploited for a therapeutic intervention. To this end, we performed genome-wide analyses to identify YAP1 occupied sites in cancer cell lines representing different YAP1/Hippo pathway tumor etiologies and in non-transformed fibroblasts. Our data demonstrate that YAP1 activity is mediated predominantly via TEAD transcription factors supporting the importance of TEADs as main mediators of YAP1-coactivator activity. We further show that YAP1 and TEAD1 exert their transcriptional control via binding to enhancers, leading to characteristic chromatin changes and distal activation of genes. By linking enhancers to genes, we provide a list of novel YAP1 target genes in an oncogenic setting that we show can readily be exploited in tumor classification and provides a foundation for further investigations.