Micro RNAs

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MicroRNAs silence gene expression by repressing protein expression and/or by promoting mRNA decay.
Review article
Behm-Ansmant I, et al. Cold Spring Harb Symp Quant Biol. 2006.
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Abstract

microRNAs (miRNAs) represent a novel class of genome-encoded eukaryotic regulatory RNAs that silence gene expression posttranscriptionally. Although the proteins mediating miRNA biogenesis and function have been identified, the precise mechanism by which miRNAs regulate the expression of target mRNAs remains unclear. We summarize recent work from our laboratory demonstrating that miRNAs silence gene expression by at least two independent mechanisms: by repressing translation and/or by promoting mRNA degradation. In Drosophila, both mechanisms require Argonaute 1 (AGO1) and the P-body component GW182. Moreover, mRNA degradation by miRNAs is effected by the enzymes involved in general mRNA decay, including deadenylases and decapping enzymes, which also localize to P bodies. Our findings suggest a model for miRNA function in which AGO1 associates with miRNA targets through miRNA:mRNA base-pairing interactions. GW182 interacts with AGO1 and recruits deadenylases and decapping enzymes, leading to mRNA degradation. However, not all miRNA targets are degraded: Some stay in a translationally silent state, from which they may eventually be released. We propose that the final outcome of miRNA regulation (i.e., degradation vs. translational repression) is influenced by other RNA-binding proteins interacting with the targeted mRNA.
PMID 17381335 [Indexed for MEDLINE]

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How do microRNAs regulate gene expression?
Review article
Cannell IG, et al. Biochem Soc Trans. 2008.
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Abstract

miRNAs (microRNAs) are short non-coding RNAs that regulate gene expression post-transcriptionally. They generally bind to the 3'-UTR (untranslated region) of their target mRNAs and repress protein production by destabilizing the mRNA and translational silencing. The exact mechanism of miRNA-mediated translational repression is yet to be fully determined, but recent data from our laboratory have shown that the stage of translation which is inhibited by miRNAs is dependent upon the promoter used for transcribing the target mRNA. This review focuses on understanding how miRNA repression is operating in light of these findings and the questions that still remain.
PMID 19021530 [Indexed for MEDLINE]
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Target-specific requirements for enhancers of decapping in miRNA-mediated gene silencing.
Eulalio A, et al. Genes Dev. 2007.
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Abstract

microRNAs (miRNAs) silence gene expression by suppressing protein production and/or by promoting mRNA decay. To elucidate how silencing is accomplished, we screened an RNA interference library for suppressors of miRNA-mediated regulation in Drosophila melanogaster cells. In addition to proteins known to be required for miRNA biogenesis and function (i.e., Drosha, Pasha, Dicer-1, AGO1, and GW182), the screen identified the decapping activator Ge-1 as being required for silencing by miRNAs. Depleting Ge-1 alone and/or in combination with other decapping activators (e.g., DCP1, EDC3, HPat, or Me31B) suppresses silencing of several miRNA targets, indicating that miRNAs elicit mRNA decapping. A comparison of gene expression profiles in cells depleted of AGO1 or of individual decapping activators shows that approximately 15% of AGO1-targets are also regulated by Ge-1, DCP1, and HPat, whereas 5% are dependent on EDC3 and LSm1-7. These percentages are underestimated because decapping activators are partially redundant. Furthermore, in the absence of active translation, some miRNA targets are stabilized, whereas others continue to be degraded in a miRNA-dependent manner. These findings suggest that miRNAs mediate post-transcriptional gene silencing by more than one mechanism.
PMID 17901217 [Indexed for MEDLINE]

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Argonaute-mediated translational repression (and activation).
Review article
Iwasaki S, et al. Fly (Austin). 2009 Jul-Sep.
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Abstract

MicroRNAs (miRNAs) downregulate the expression of their target genes by inducing translational repression and/or mRNA decay. Under specific conditions, miRNAs can even activate translation of their target mRNAs. These processes occur via miRNA-protein complexes, or RNA-induced silencing complexes (RISCs), which contain Argonaute (Ago) subfamily protein as a core component. However, detailed mechanisms of miRNA-mediated translational regulation remain unclear. We recently reported that, in Drosophila, both of the two Ago proteins, Ago1 and Ago2, can repress translation of the target mRNAs, but by remarkably different mechanisms. Furthermore, we here show that Ago2, but not Ago1, can activate translation of the target mRNAs when they lack the poly(A) tail, suggesting that the length of poly(A) tail is an important determinant for the consequences of Ago2 function. This review focuses on how miRNAs regulate translation in light of these new findings.
PMID 19556851 [Indexed for MEDLINE]

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MicroRNAs: biogenesis and molecular functions.
Review article
Liu X, et al. Brain Pathol. 2008.
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Abstract

Small regulatory RNAs are essential and ubiquitous riboregulators that are the key mediators of RNA interference (RNAi). They include microRNAs (miRNAs) and short-interfering RNAs (siRNAs), classes of approximately 22 nucleotide RNAs. miRNAs and siRNAs bind to Argonaute proteins and form effector complexes that regulate gene expression; in animals, this regulation occurs primarily at the post-transcriptional level. In this review, we will discuss our current understanding of how miRNA and siRNAs are generated and how they function to silence gene expression, focusing on animal and, in particular, mammalian miRNAs.
PMID 18226106 [Indexed for MEDLINE]
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Journal ListJ Transl Medv.14; 2016PMC4873990

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J Transl Med. 2016; 14: 143.
Published online 2016 May 20. doi: 10.1186/s12967-016-0893-x
PMCID: PMC4873990
PMID: 27197967
Regulatory mechanisms of microRNA expression
Lyudmila F. Gulyaevacorresponding author and Nicolay E. Kushlinskiy
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This article has been cited by other articles in PMC.
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Abstract

MicroRNAs (miRs, miRNAs) are small molecules of 18–22 nucleotides that serve as important regulators of gene expression at the post-transcriptional level. One of the mechanisms through which miRNAs regulate gene expression involves the interaction of their “seed” sequences primarily with 3′-end and more rarely with 5′-end, of mRNA transcribed from target genes. Numerous studies over the past decade have been devoted to quantitative and qualitative assessment of miRNAs expression and have shown remarkable changes in miRNA expression profiles in various diseases. Thus, profiling of miRNA expression can be an important tool for diagnostics and treatment of disease. However, less attention has been paid towards understanding the underlying reasons for changes in miRNA expression, especially in cancer cells. The purpose of this review is to analyze and systematize current data that explains reasons for changes in the expression of miRNAs. The review will cover both transcriptional (changes in gene expression and promoter hypermethylation) and post-transcriptional (changes in miRNA processing) mechanisms of regulation of miRNA expression, as well as effects of endogenous (hormones, cytokines) and exogenous (xenobiotics) compounds on the miRNA expression. The review will summarize the complex multilevel regulation of miRNA expression, in relation to cell type, physiological state of the body and various external factors.
Keywords: MicroRNA expression, Gene expression, Hypermethylation, Cancer, MiRNA processing, Cytokines, Xenobiotics, Nuclear receptors

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Journal ListCurr Genomicsv.11(7); 2010 NovPMC3048316

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Curr Genomics. 2010 Nov; 11(7): 537–561.
doi: 10.2174/138920210793175895
PMCID: PMC3048316
PMID: 21532838
MicroRNA: Biogenesis, Function and Role in Cancer
Leigh-Ann MacFarlane and Paul R. Murphy*
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Abstract

MicroRNAs are small, highly conserved non-coding RNA molecules involved in the regulation of gene expression. MicroRNAs are transcribed by RNA polymerases II and III, generating precursors that undergo a series of cleavage events to form mature microRNA. The conventional biogenesis pathway consists of two cleavage events, one nuclear and one cytoplasmic. However, alternative biogenesis pathways exist that differ in the number of cleavage events and enzymes responsible. How microRNA precursors are sorted to the different pathways is unclear but appears to be determined by the site of origin of the microRNA, its sequence and thermodynamic stability. The regulatory functions of microRNAs are accomplished through the RNA-induced silencing complex (RISC). MicroRNA assembles into RISC, activating the complex to target messenger RNA (mRNA) specified by the microRNA. Various RISC assembly models have been proposed and research continues to explore the mechanism(s) of RISC loading and activation. The degree and nature of the complementarity between the microRNA and target determine the gene silencing mechanism, slicer-dependent mRNA degradation or slicer-independent translation inhibition. Recent evidence indicates that P-bodies are essential for microRNA-mediated gene silencing and that RISC assembly and silencing occurs primarily within P-bodies. The P-body model outlines microRNA sorting and shuttling between specialized P-body compartments that house enzymes required for slicer –dependent and –independent silencing, addressing the reversibility of these silencing mechanisms. Detailed knowledge of the microRNA pathways is essential for understanding their physiological role and the implications associated with dysfunction and dysregulation.
Keywords: MicroRNA, RNA interference (RNAi), Post-transcriptional gene regulation, Cancer.
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INTRODUCTION

MicroRNA (miRNA), originally discovered in Caenorhabditis elegans, is found in most eukaryotes, including humans [1-3]. It is predicted that miRNA account for 1-5% of the human genome and regulate at least 30% of protein-coding genes [4-8]. To date, 940 distinct miRNAs molecules have been identified within the human genome [9-12] (http://microrna.sanger.ac.uk accessed July 20, 2010). Although little is currently known about the specific targets and biological functions of miRNA molecules thus far, it is evident that miRNA plays a crucial role in the regulation of gene expression controlling diverse cellular and metabolic pathways [13-19].

MiRNA are small, evolutionary conserved, single-stranded, non-coding RNA molecules that bind target mRNA to prevent protein production by one of two distinct mechanisms. Mature miRNA is generated through two-step cleavage of primary miRNA (pri-miRNA), which incorporates into the effector complex RNA-induced silencing complex (RISC). The miRNA functions as a guide by base-pairing with target mRNA to negatively regulate its expression. The level of complementarity between the guide and mRNA target determines which silencing mechanism will be employed; cleavage of target messenger RNA (mRNA) with subsequent degradation or translation inhibition