A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers.
A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers.
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基因多态性靶向的启动子近端转录物控制人类癌症中的E-钙粘蛋白沉默
DOI：
10.1038/ncomms15622
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发表时间：
2017-05-30
影响因子：
16.6
通讯作者：
Catapano CV
中科院分区：
文献类型：
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作者：
Pisignano G;Napoli S;Magistri M;Mapelli SN;Pastori C;Di Marco S;Civenni G;Albino D;Enriquez C;Allegrini S;Mitra A;D'Ambrosio G;Mello-Grand M;Chiorino G;Garcia-Escudero R;Varani G;Carbone GM;Catapano CV
长链非编码RNA是表观遗传机制中的新兴参与者，在发育和疾病中发挥关键作用。在这里，我们发现了一个复杂的网络，包括启动子相关的非编码RNA（paRNA），microRNA和表观遗传调节因子，控制上皮癌中肿瘤抑制因子E-钙粘蛋白的转录。E-cadherin沉默依赖于在paRNA和microRNA引导的Argonaute 1之间形成复合物，该复合物一起募集SUV 39 H1并在基因启动子中诱导抑制性染色质修饰。与癌症风险增加相关的单核苷酸多态性（rs 16260）改变了paRNA的二级结构，风险等位基因促进了microRNA引导的Argonaute 1复合物的组装和基因沉默。总的来说，这些数据证明了paRNA在E-钙粘蛋白调节中的作用以及非编码遗传变体对其功能的影响。基于paRNA的表观遗传网络的失调可能有助于癌症和其他疾病，使其成为药物发现的有希望的靶点。启动子近端转录物被认为是调节转录的顺式作用元件。在这里，作者提供的证据表明，启动子近端RNA与其他表观遗传调节因子结合，控制上皮癌中E-钙粘蛋白的转录。
Long noncoding RNAs are emerging players in the epigenetic machinery with key roles in development and diseases. Here we uncover a complex network comprising a promoter-associated noncoding RNA (paRNA), microRNA and epigenetic regulators that controls transcription of the tumour suppressor E-cadherin in epithelial cancers. E-cadherin silencing relies on the formation of a complex between the paRNA and microRNA-guided Argonaute 1 that, together, recruit SUV39H1 and induce repressive chromatin modifications in the gene promoter. A single nucleotide polymorphism (rs16260) linked to increased cancer risk alters the secondary structure of the paRNA, with the risk allele facilitating the assembly of the microRNA-guided Argonaute 1 complex and gene silencing. Collectively, these data demonstrate the role of a paRNA in E-cadherin regulation and the impact of a noncoding genetic variant on its function. Deregulation of paRNA-based epigenetic networks may contribute to cancer and other diseases making them promising targets for drug discovery. Promoter-proximal transcripts have been proposed to act as cis-acting elements regulating transcription. Here, the authors provide evidence that a promoter-proximal RNA, in combination with other epigenetic regulators, controls transcription of E-cadherin in epithelial cancers.