Nuclear functions of mammalian MicroRNAs in gene regulation, immunity and cancer

Abstract

MicroRNAs (miRNAs) are endogenous non-coding RNAs that contain approximately 22 nucleotides. They serve as key regulators in various biological processes and their dysregulation is implicated in many diseases including cancer and autoimmune disorders. It has been well established that the maturation of miRNAs occurs in the cytoplasm and miRNAs exert post-transcriptional gene silencing (PTGS) via RNA-induced silencing complex (RISC) pathway in the cytoplasm. However, numerous studies reaffirm the existence of mature miRNA in the nucleus, and nucleus-cytoplasm transport mechanism has also been illustrated. Moreover, active regulatory functions of nuclear miRNAs were found including PTGS, transcriptional gene silencing (TGS), and transcriptional gene activation (TGA), in which miRNAs bind nascent RNA transcripts, gene promoter regions or enhancer regions and exert further effects via epigenetic pathways. Based on existing interaction rules, some miRNA binding sites prediction software tools are developed, which are evaluated in this article. In addition, we attempt to explore and review the nuclear functions of miRNA in immunity, tumorigenesis and invasiveness of tumor. As a non-canonical aspect of miRNA action, nuclear miRNAs supplement miRNA regulatory networks and could be applied in miRNA based therapies.

Let‐7a‐regulated translational readthrough of mammalian AGO 1 generates a micro RNA pathway inhibitor

“…We demonstrate this using let-7a inhibitor and let-7a overexpression system in both endogenous (Ago1x) and exogenous (luciferase-based assay) systems. miRNAs are also reported to regulate transcription in the nucleus (Liu et al, 2018). This is in agreement with the fact that rabbit reticulocyte lysate (both nuclease-treated and untreated) contains let-7a miRNA (Ricci et al, 2011).…”

Transcriptional memory in skeletal muscle. Don't forget (to) exercise

“…Nuclear localized miRNAs were found capable both to suppress and to stimulate transcriptional expression at distinct gene loci, involving direct and indirect interference pathways. Target RNA levels in the nucleus can be reduced through site‐specific cleavage by AGO slicer activity (Gagnon et al, 2014), enabling nuclear RISC not only to mediate degradation of mRNAs but also of diverse noncoding nuclear RNA species that serve gene regulatory functions (H. Liu et al, 2018). By repressing the repressors, specific nuclear miRNAs thus can indirectly promote transcriptional gene activation, for example, via miRNA‐directed degradation of miRNA precursors, long noncoding RNAs, and natural antisense transcripts (NATs) that convey epigenetic silencing of distinct gene loci in either a cis or a trans manner (Beiter, Reich, Williams, & Simon, 2009; H. Liu et al, 2018; Roberts, 2014).…”

Anticancer potential of naturally occurring immunoepigenetic modulators: A promising avenue?

“…miRNAs are from 19 to 25 nucleotides in length that post‐transcriptionally repress messenger RNA (mRNA) expression levels. A large amount of data reveals that the deregulation of miRNA expression profiles is associated with tumorigenesis and plays a key role in immunosuppression …”

“…A large amount of data reveals that the deregulation of miRNA expression profiles is associated with tumorigenesis and plays a key role in immunosuppression. 9,15 Epigenetic alterations can be reversed in part by drugs that target the enzymes involved in writing, erasing, or reading epigenetic marks. Although dozens of synthetic and natural compounds have been described in preclinical and clinical trials, currently, there are only 6 US Food and Drug Administration (FDA)-approved epigenetic drugs (Supporting Table 1).…”