Small RNA-directed transcriptional control: New insights into mechanisms and therapeutic applications

Pastori, Chiara; Magistri, Marco; Napoli, Sara; Carbone, Giuseppina M.; Catapano, Carlo V.

doi:10.4161/cc.9.12.12049

Cited by 12 publications

(7 citation statements)

References 83 publications

(208 reference statements)

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“…Our result suggest that altering the sequence, structure and, therefore, function of paRNAs provides an additional and still unexplored way by which polymorphic sites and somatic mutations in noncoding regions influence the epigenetic landscape and impact on human disease. These results also support the development of inhibitors targeting these ncRNAs for gene-selective transcriptional reprogramming28346061, since knockdown of S-paRNA reactivates CDH1 expression in prostate cancer cells and impairs their proliferative, clonogenic and stem-likeness. Reprogramming transcription of individual genes through this approach would have broad implications for epigenetic therapy of cancer and other diseases.…”

Section: Discussionsupporting

confidence: 65%

A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 65%

A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers

et al. 2017

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“…In addition, we showed recently that Myc could be epigenetically silenced with high efficiency by promoter-targeting siRNAs (28). Transcriptional silencing by promoter-targeting siRNAs could provide an effective means to modulate gene expression in addition to canonical posttranscriptional RNA interference (RNAi) directed to mRNAs (29). Our approach was based on the presence of a cis-acting noncoding promoterassociated RNA (paRNA) overlapping the Myc transcription start site (TSS) and positively regulating transcription initiation (28).…”

Section: /Cd24mentioning

confidence: 99%

RNAi-Mediated Silencing of Myc Transcription Inhibits Stem-like Cell Maintenance and Tumorigenicity in Prostate Cancer

et al. 2013

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Several studies link disease progression, recurrence, and treatment failures to the cancer stem-like cell (CSC) subpopulation within the heterogeneous tumor cell population. Myc is a transcription factor having a central function in stem cell biology and in human cancers. Hence, Myc represents an attractive target to develop CSC-specific therapies. Recent findings suggest that Myc transcription can be silenced using an RNA interference (RNAi)-based strategy that targets noncoding promoter-associated RNA (paRNA) overlapping the transcription start site. In this study, we investigated the effects of silencing Myc transcription on prostate CSC in cell culture and xenograft models of human prostate cancer. Treatment with an effective promotertargeting siRNA reduced the fraction of CSCs, leading to reduced self-renewal, tumor-initiating, and metastatic capability. Combined analysis of stem-like cells and senescence markers indicated that Myc silencing triggered a phenotypic shift and senescence in the CSC subpopulation. Notably, systemic delivery of the promoter-targeting siRNA in the xenograft model produced a striking suppression in the development of prostate tumors. Our results support a pivotal role for Myc in CSC maintenance and show that Myc targeting via RNAi-based transcriptional silencing can trigger CSC senescence and loss of their tumor-initiating capability. More generally, our findings demonstrate the efficacy of RNAi-based transcriptional strategies and the potential to target regulatory noncoding paRNAs for therapeutic applications. Cancer Res; 73(22);

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“…Although the mechanisms of lncRNAs as key regulators of gene expression are yet to be fully elucidated, a common emerging theme is that lncRNAs form RNA-protein complexes to exert their regulatory functions. In some cases NATs are reported to modulate DNA accessibility by binding to chromatin-modifying complexes and sequestration of transcription factor, which in turn influence gene expression (Guttman and Rinn, 2012; Pastori et al, 2010; Rinn and Chang, 2012; Wang and Chang, 2011). Therefore, in order to understand the function of lncRNAs it is of crucial importance to identify the interacting proteins.…”

Section: Introductionmentioning

confidence: 99%

Antisense RNA Controls LRP1 Sense Transcript Expression through Interaction with a Chromatin-Associated Protein, HMGB2

et al. 2015

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SUMMARY Long non-coding RNAs (lncRNAs) including natural antisense transcripts (NATs) are expressed more extensively than previously anticipated, and have widespread roles in regulating gene expression. Nevertheless, the molecular mechanisms of action of the majority of NATs remain largely unknown. Here we identify a NAT of Low-density lipoprotein receptor-related protein 1 (Lrp1), referred to as Lrp1-AS, that negatively regulates Lrp1 expression. We show that Lrp1-AS directly binds to High mobility group box 2 (Hmgb2) and inhibits the activity of Hmgb2 to enhance Srebp1a-dependent transcription of Lrp1. Short oligonucleotides targeting Lrp1-AS inhibit the interaction of antisense transcript and Hmgb2 protein, and increase Lrp1 expression by enhancing Hmgb2 activity. qRT-PCR analysis of Alzheimer’s disease brain samples and aged-matched controls revealed upregulation of LRP1-AS and downregulation of LRP1. Our data suggest a new regulatory mechanism whereby a NAT interacts with a ubiquitous chromatin-associated protein to modulate its activity in a locus-specific fashion.

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Small RNA-directed transcriptional control: New insights into mechanisms and therapeutic applications

Cited by 12 publications

References 83 publications

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

RNAi-Mediated Silencing of Myc Transcription Inhibits Stem-like Cell Maintenance and Tumorigenicity in Prostate Cancer

Antisense RNA Controls LRP1 Sense Transcript Expression through Interaction with a Chromatin-Associated Protein, HMGB2

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