Diepenbruck Maren, Waldmeier Lorenz, Ivanek Robert, Berninger Philipp, Arnold Phil, van Nimwegen Erik, Christofori Gerhard
Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
J Cell Sci. 2014 Apr 1;127(Pt 7):1523-36. doi: 10.1242/jcs.139865. Epub 2014 Feb 19.
The cellular changes during an epithelial-mesenchymal transition (EMT) largely rely on global changes in gene expression orchestrated by transcription factors. Tead transcription factors and their transcriptional co-activators Yap and Taz have been previously implicated in promoting an EMT; however, their direct transcriptional target genes and their functional role during EMT have remained elusive. We have uncovered a previously unanticipated role of the transcription factor Tead2 during EMT. During EMT in mammary gland epithelial cells and breast cancer cells, levels of Tead2 increase in the nucleus of cells, thereby directing a predominant nuclear localization of its co-factors Yap and Taz via the formation of Tead2-Yap-Taz complexes. Genome-wide chromatin immunoprecipitation and next generation sequencing in combination with gene expression profiling revealed the transcriptional targets of Tead2 during EMT. Among these, zyxin contributes to the migratory and invasive phenotype evoked by Tead2. The results demonstrate that Tead transcription factors are crucial regulators of the cellular distribution of Yap and Taz, and together they control the expression of genes critical for EMT and metastasis.
上皮-间质转化（EMT）过程中的细胞变化很大程度上依赖于由转录因子精心编排的基因表达全局变化。Tead转录因子及其转录共激活因子Yap和Taz先前已被认为与促进EMT有关；然而，它们直接的转录靶基因以及在EMT过程中的功能作用仍不清楚。我们发现了转录因子Tead2在EMT过程中一个先前未预料到的作用。在乳腺上皮细胞和乳腺癌细胞的EMT过程中，Tead2在细胞核中的水平升高，从而通过形成Tead2-Yap-Taz复合物引导其辅助因子Yap和Taz主要定位于细胞核。全基因组染色质免疫沉淀和下一代测序结合基因表达谱分析揭示了EMT过程中Tead2的转录靶标。其中，斑联蛋白有助于Tead2诱发的迁移和侵袭表型。结果表明，Tead转录因子是Yap和Taz细胞分布的关键调节因子，它们共同控制对EMT和转移至关重要的基因的表达。
