Issue&Volume: 2022-07-14

  这些发现例证了Zhì癌信号如何调节DNA去Jiǎ基化的位点特异性以促进肿瘤的发生,并暗示TET1是调节YAP信号在生理和疾病方面的潜在靶Biāo。

  Source: https://www.nature.com/articles/s41588-022-01119-7

  Author: Wu, Bo-Kuan, Mei, Szu-Chieh, Chen, Elizabeth H., Zheng, Yonggang, Pan, Duojia

  据了解,表观遗传重塑对致癌物诱导的细胞转化和恶性肿瘤至关重要。与组蛋白翻译后修饰相比,DNA甲基化如何被致ái信号Zhòng塑仍然知之甚少。肿瘤蛋白YAP是介DǎoHippo信Hào传导的TEAD转录因子的协同激活因子,在人类癌症中被广泛激活。

  附:英文原文

  Title: YAP induces an oncogenic transcriptional program through TET1-mediated epigenetic remodeling in liver growth and tumorigenesis

  DOI: 10.1038/s41588-022-01119-7

  Abstract: Epigenetic remodeling is essential for oncogene-induced cellular transformation and malignancy. In contrast to histone post-translational modifications, how DNA methylation is remodeled by oncogenic signaling remains poorly understood. The oncoprotein YAP, a coactivator of the TEAD transcription factors mediating Hippo signaling, is widely activated in human cancers. Here, we identify the 5-methylcytosine dioxygenase TET1 as a direct YAP target and a master regulator that coordinates the genome-wide epigenetic and transcriptional reprogramming of YAP target genes in the liver. YAP activation induces the expression of TET1, which physically interacts with TEAD to cause regional DNA demethylation, histone H3K27 acetylation and chromatin opening in YAP target genes to facilitate transcriptional activation. Loss of TET1 not only reverses YAP-induced epigenetic and transcriptional changes but also suppresses YAP-induced hepatomegaly and tumorigenesis. These findings exemplify how oncogenic signaling regulates the site specificity of DNA demethylation to promote tumorigenesis and implicate TET1 as a potential target for modulating YAP signaling in physiology and disease. 

  研究人员确定5-甲基胞嘧啶双加氧酶TET1是YAP的直接靶点,也是协调肝脏中YAP靶基因De全基因组表观遗传和转录重编程的核心调节因子。YAP激活诱导TET1的表达,TET1与TEAD发生物理作用,导致YAP靶基因的区域DNA去甲基化、组蛋白H3K27乙酰化和染色质开放,从而促进转录激活。TET1的缺失不仅逆转了YAP诱导的表观遗传和转录变化,而且还抑制了YAP诱导的肝脏肿大和肿瘤发生。

  美国德克萨斯大学Duojia Pan课题Zǔ发现,YAP通过TET1介导的表观遗传重塑在肝脏生长和Zhǒng瘤发生中诱导致癌性转录程序。2022年7月14日,《自然—遗Zhuàn学》杂志在线发表了这项成果。