Abstract
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.
Highlights
Long noncoding RNAs are emerging players in the epigenetic machinery with key roles in development and diseases
Using the selective 20-hydroxyl acylation and primer extension (SHAPE)-determined structures to estimate the likelihood of the isomiR-promoter-associated noncoding RNA (paRNA) interaction, we find that the C to A exchange at position À 160 decreases the base-pairing probability for the isomiR-4534 binding site hairpin from 499% to 90–95%, indicating a greater predisposition of the hairpin to unwind and allow access to the isomiR-4534 by strand invasion (Supplementary Fig. 10)
We show that transcriptional silencing and activation of CDH1 are at least partially controlled by an epigenetic switch that relies on S and AS-transcripts generated from distinct initiation sites upstream of the gene transcription start site (TSS) (Fig. 8)
Summary
Long noncoding RNAs are emerging players in the epigenetic machinery with key roles in development and diseases. 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. These data demonstrate the role of a paRNA in E-cadherin regulation and the impact of a noncoding genetic variant on its function. We show the involvement of paRNAs in the transcriptional regulation of a key tumour suppressor gene and how the impact of a functional noncoding genetic variant on epigenetic gene silencing and tumour progression is mediated by the effect on the secondary structure of a promoter-proximal transcript. Our work suggests that deregulation of paRNA-based transcriptional mechanisms could contribute to epigenetic silencing of tumour suppressor genes and disease progression in cancer patients
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