RNA Networks that Regulate mRNA Expression and their Potential as Drug Targets

Abstract

Natural antisense transcripts (asRNAs) transcribed from eukaryotic genes are primarily long transcripts that do not code for proteins. Transcriptome analyses have revealed that asRNAs exhibit diverse functional roles in the regulation of gene expression. In the case of inducible genes, asRNAs epigenetically affect their expression or post-transcriptionally affect stability and translatability of their mRNAs. Many low-copy-number asRNAs regulate the expression levels of mRNAs through cis-controlling elements in the mRNA in concert with trans-acting factors, such as RNA-binding proteins and microRNAs. Recently, a competitive endogenous RNA (ceRNA) hypothesis was postulated as the basis of a functional network, comprising mRNAs, asRNAs, and microRNAs. This network finely tunes mRNA expression by common microRNA-responsive elements being present among mRNAs and asRNAs, permitting the redirection of microRNAs between the two. Examples of the ceRNA-mediated cross-regulation of mRNA expression are observed in the phosphatase and tensin homolog mRNA network and the interferon-alpha1 mRNA network. In such regulatory RNA networks, an mRNA, its corresponding asRNAs (high specificity), microRNAs (low specificity), and RNA-binding proteins mutually interact. Both asRNAs and microRNAs are involved in the pathogenesis or pathophysiology of various diseases, such as cancer, inflammation, and infection. Simple disruption of an asRNA or a microRNA can often show off-target effects due to complicated interactions inside and outside the regulatory RNA networks. Therefore, drugs that target asRNAs should be developed to minimize off-target effects and to target interactions that are dysregulated in disease.

c-Myc/microRNA-17-92 Axis Phase-Dependently Regulates PTEN and p21 Expression via ceRNA during Reprogramming to Mouse Pluripotent Stem Cells

“…We hypothesized that PTEN mRNA and other miR-17-92 targets, including p21 mRNA, may act as competing endogenous RNAs (ceRNAs), which are RNAs sharing miRNA recognition elements (MREs) with other RNAs (such as mRNA and long non-coding RNA), as common targets against the miRNA [ 20 ]. Depending on the miRNA affinity, variable post-transcriptional regulation of one or more genes may occur among all miRNA targets [ 20 , 21 ]. To examine the above hypothesis, we constructed lentiviral vectors expressing a DsRed coding region fused with each segment of the six consecutive regions (a–f) or the full-length PTEN 3′ UTR.…”

“…In general, miRNAs inhibited the stability and translation of mRNAs by forming an RNA-induced silencing complex that bound to a partially complementary sequence called MRE in their target genes. ceRNAs are a variety of RNA, including long non-coding RNA and mRNA with the same MRE, and they competitively share the same miRNA pool [ 20 , 21 ]. During iPSC reprogramming, we demonstrated that the miR-17-92-dependent downregulation of PTEN was influenced by p21 transcript levels, suggesting that miR-17-92 preferentially repressed p21 rather than PTEN in the early-to-mid phase when p21 mRNA expression was upregulated.…”

Pathogen-associated regulatory non-coding RNAs and oncogenesis

“…Upon inhibition of the miR-200 family in a gastric carcinoma cell line, the up-regulated repressors suppress E-cadherin expression, resulting in EMT (95). Indeed, transfection of BARF0, EBNA1, and LMP2A expression plasmids downregulated the transcription of pri-miR-200 RNAs, whereas EBER1 post-transcriptionally inhibited miR-200 action (95), possibly acting as a ceRNA (competing endogenous RNA) to sequester the miR-200 family (96,97).…”