EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells
EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells
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DOI：
10.1038/s41419-020-2340-4
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发表时间：
2020-02-24
影响因子：
9
通讯作者：
Schneider-Stock, Regine
中科院分区：
文献类型：
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作者：
Lindner, Pablo;Paul, Sushmita;Schneider-Stock, Regine
表观遗传失调显著触发与肿瘤侵袭性相关的机制，如上皮-间质转化（EMT）。由于EMT是一个高度复杂但可逆的事件，因此表观遗传过程（如DNA甲基化或染色质改变）必须参与其调控。最近描述了细胞周期调节因子p21的丢失与EMT特征的获得和主EMT转录因子ZEB 1的上调相关。在这项研究中，结合不同的体外和体内技术进行了计算机分析，以鉴定和验证ZEB 1的新表观遗传靶点，并证明ZEB 1对SETD 1B的直接转录调控。绒毛膜尿囊膜试验作为体内模型来分析ZEB1/SETD1B相互作用。CRC患者数据的生物信息学分析用于检查临床条件下的ZEB 1/SETD1B网络，并且在生理和病理条件下对ZEB 1/SETD1B网络进行建模。因此，我们确定了ZEB1表达的自我增强环，并发现SETD1B相关的活性染色质标记H3K4me3在EMT细胞中的ZEB1启动子处富集。此外，CRC患者数据的临床评估显示，ZEB 1和SETD 1B的同时高表达与最差预后相关。在这里，我们报告，染色质修饰剂的表达显着失调EMT细胞。SETD 1B被鉴定为体外和体内新的ZEB 1靶点。我们的研究证明了ZEB 1在结直肠肿瘤细胞表观遗传景观中的激活作用的一个新例子。
Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial-mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell cycle regulator p21 was associated with a gain in EMT characteristics and an upregulation of the master EMT transcription factor ZEB1. In this study, in silico analysis was performed in combination with different in vitro and in vivo techniques to identify and verify novel epigenetic targets of ZEB1, and to proof the direct transcriptional regulation of SETD1B by ZEB1. The chorioallantoic-membrane assay served as an in vivo model to analyze the ZEB1/SETD1B interaction. Bioinformatical analysis of CRC patient data was used to examine the ZEB1/SETD1B network under clinical conditions and the ZEB1/SETD1B network was modeled under physiological and pathological conditions. Thus, we identified a self-reinforcing loop for ZEB1 expression and found that the SETD1B associated active chromatin mark H3K4me3 was enriched at the ZEB1 promoter in EMT cells. Moreover, clinical evaluation of CRC patient data showed that the simultaneous high expression of ZEB1 and SETD1B was correlated with the worst prognosis. Here we report that the expression of chromatin modifiers is remarkably dysregulated in EMT cells. SETD1B was identified as a new ZEB1 target in vitro and in vivo. Our study demonstrates a novel example of an activator role of ZEB1 for the epigenetic landscape in colorectal tumor cells.