Promoter-level expression clustering identifies time development of transcriptional regulatory cascades initiated by ErbB receptors in breast cancer cells
Promoter-level expression clustering identifies time development of transcriptional regulatory cascades initiated by ErbB receptors in breast cancer cells
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DOI：
10.1038/srep11999
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发表时间：
2015-07-16
影响因子：
4.6
通讯作者：
Furlanello, Cesare
中科院分区：
文献类型：
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作者：
Mina, Marco;Magi, Shigeyuki;Furlanello, Cesare
CAGE（Cap Analysis of Gene Expression，基因表达帽分析）时程分析是由FANTOM 5 Consortium提出的，旨在扩展对在启动子调控水平上促进细胞状态转换的事件序列的理解。为了确定最突出的转录调控诱导的生长因子在人类乳腺癌中，我们在这里应用复杂性不变的动态时间规整基序富集（CIDER）分析方法的CAGE时间过程数据集的MCF-7细胞刺激表皮生长因子（EGF）或heregulin（HRG）。我们确定了一个多层次的级联调节植根于血清反应因子（SRF）转录因子，连接MAPK介导的转导的HRG刺激的MAPK途径的负调控的DUSP家族磷酸酶的成员。这一发现证实了AP-1家族成员FOS和FOSL 1在响应HRG诱导的基因表达中的已知主要作用。此外，我们确定了一个新的潜在的调节DUSP 5和RARA（已知拮抗雌激素受体诱导的转录调节）的AP-1复合物的活性，特异性HRG反应。结果表明AP-1调节的差异决定了ErbB受体刺激的乳腺癌细胞的细胞变化。
The analysis of CAGE (Cap Analysis of Gene Expression) time-course has been proposed by the FANTOM5 Consortium to extend the understanding of the sequence of events facilitating cell state transition at the level of promoter regulation. To identify the most prominent transcriptional regulations induced by growth factors in human breast cancer, we apply here the Complexity Invariant Dynamic Time Warping motif EnRichment (CIDER) analysis approach to the CAGE time-course datasets of MCF-7 cells stimulated by epidermal growth factor (EGF) or heregulin (HRG). We identify a multi-level cascade of regulations rooted by the Serum Response Factor (SRF) transcription factor, connecting the MAPK-mediated transduction of the HRG stimulus to the negative regulation of the MAPK pathway by the members of the DUSP family phosphatases. The finding confirms the known primary role of FOS and FOSL1, members of AP-1 family, in shaping gene expression in response to HRG induction. Moreover, we identify a new potential regulation of DUSP5 and RARA (known to antagonize the transcriptional regulation induced by the estrogen receptors) by the activity of the AP-1 complex, specific to HRG response. The results indicate that a divergence in AP-1 regulation determines cellular changes of breast cancer cells stimulated by ErbB receptors.