-
International Journal of Molecular... Dec 2019MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at the post-transcriptional level either by inhibiting messenger RNA... (Review)
Review
MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at the post-transcriptional level either by inhibiting messenger RNA (mRNA) translation or by promoting mRNA degradation. The outcome of a myriad of physiological processes and pathologies, including cancer, cardiovascular and metabolic diseases, relies highly on miRNAs. However, deciphering the precise roles of specific miRNAs in these pathophysiological contexts is challenging due to the high levels of complexity of their actions. Indeed, regulation of mRNA expression by miRNAs is frequently cell/organ specific; highly dependent on the stress and metabolic status of the organism; and often poorly correlated with miRNA expression levels. Such biological features of miRNAs suggest that various regulatory mechanisms control not only their expression, but also their activity and/or bioavailability. Several mechanisms have been described to modulate miRNA action, including genetic polymorphisms, methylation of miRNA promoters, asymmetric miRNA strand selection, interactions with RNA-binding proteins (RBPs) or other coding/non-coding RNAs. Moreover, nucleotide modifications (A-to-I or C-to-U) within the miRNA sequences at different stages of their maturation are also critical for their functionality. This regulatory mechanism called "RNA editing" involves specific enzymes of the adenosine/cytidine deaminase family, which trigger single nucleotide changes in primary miRNAs. These nucleotide modifications greatly influence a miRNA's stability, maturation and activity by changing its specificity towards target mRNAs. Understanding how editing events impact miRNA's ability to regulate stress responses in cells and organs, or the development of specific pathologies, e.g., metabolic diseases or cancer, should not only deepen our knowledge of molecular mechanisms underlying complex diseases, but can also facilitate the design of new therapeutic approaches based on miRNA targeting. Herein, we will discuss the current knowledge on miRNA editing and how this mechanism regulates miRNA biogenesis and activity.
Topics: Animals; Gene Expression Regulation; Humans; MicroRNAs; Neoplasms; RNA Editing
PubMed: 31835747
DOI: 10.3390/ijms20246249 -
International Journal of Molecular... Mar 2020Altered gene expression is the primary molecular mechanism responsible for the pathological processes of human diseases, including cancer. MicroRNAs (miRNAs) are... (Review)
Review
Altered gene expression is the primary molecular mechanism responsible for the pathological processes of human diseases, including cancer. MicroRNAs (miRNAs) are virtually involved at the post-transcriptional level and bind to 3' UTR of their target messenger RNA (mRNA) to suppress expression. Dysfunction of miRNAs disturbs expression of oncogenic or tumor-suppressive target genes, which is implicated in cancer pathogenesis. As such, a large number of miRNAs have been found to be downregulated or upregulated in human cancers and to function as oncomiRs or oncosuppressor miRs. Notably, the molecular mechanism underlying the dysregulation of miRNA expression in cancer has been recently uncovered. The genetic deletion or amplification and epigenetic methylation of miRNA genomic loci and the transcription factor-mediated regulation of primary miRNA often alter the landscape of miRNA expression in cancer. Dysregulation of the multiple processing steps in mature miRNA biogenesis can also cause alterations in miRNA expression in cancer. Detailed knowledge of the regulatory mechanism of miRNAs in cancer is essential for understanding its physiological role and the implications of cancer-associated dysfunction and dysregulation. In this review, we elucidate how miRNA expression is deregulated in cancer, paying particular attention to the cancer-associated transcriptional and post-transcriptional factors that execute miRNA programs.
Topics: Animals; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; RNA, Messenger
PubMed: 32138313
DOI: 10.3390/ijms21051723 -
Biomedicine & Pharmacotherapy =... Jun 2021MicroRNAs (miRNAs) are a group of small non-coding RNAs that post-transcriptionally control expression of genes by targeting mRNAs. miRNA alterations partake in the... (Review)
Review
MicroRNAs (miRNAs) are a group of small non-coding RNAs that post-transcriptionally control expression of genes by targeting mRNAs. miRNA alterations partake in the establishment and progression of different types of human cancer. Consequently, expression profiling of miRNA in human cancers has correlations with cancer detection, staging, progression, and response to therapies. Particularly, amplification, deletion, abnormal pattern of epigenetic factors and the transcriptional factors that mediate regulation of primary miRNA frequently change the landscape of miRNA expression in cancer. Indeed, changes in the quantity and quality of miRNAs are associated with the initiation of cancer, its progression and metastasis. Additionally, miRNA profiling has been used to categorize genes that can affect oncogenic pathways in cancer. Here, we discuss several circulating miRNA signatures, their expression profiles in different types of cancer and their impacts on cellular processes.
Topics: Animals; Disease Progression; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms
PubMed: 33770669
DOI: 10.1016/j.biopha.2021.111528 -
Cell May 2022Cancer cells are featured with uncontrollable activation of cell cycle, and microRNA deficiency drives tumorigenesis. The RNA-dependent RNA polymerase (RDR) is essential...
Cancer cells are featured with uncontrollable activation of cell cycle, and microRNA deficiency drives tumorigenesis. The RNA-dependent RNA polymerase (RDR) is essential for small-RNA-mediated immune response in plants but is absent in vertebrates. Here, we show that ectopic expression of plant RDR1 can generally inhibit cancer cell proliferation. In many human primary tumors, abnormal microRNA isoforms with 1-nt-shorter 3' ends are widely accumulated. RDR1 with nucleotidyltransferase activity can recognize and modify the problematic AGO2-free microRNA duplexes with mononucleotides to restore their 2 nt overhang structure, which eventually rescues AGO2-loading efficiency and elevates global miRNA expression to inhibit cancer cell-cycle specifically. The broad antitumor effects of RDR1, which can be delivered by an adeno-associated virus, are visualized in multiple xenograft tumor models in vivo. Altogether, we reveal the widespread accumulation of aberrant microRNA isoforms in tumors and develop a plant RDR1-mediated antitumor stratagem by editing and repairing defective microRNAs.
Topics: Animals; Humans; Immunity; MicroRNAs; Plant Proteins; Plants; RNA-Dependent RNA Polymerase
PubMed: 35623329
DOI: 10.1016/j.cell.2022.04.030 -
Nucleic Acids Research Jan 2006The miRBase database aims to provide integrated interfaces to comprehensive microRNA sequence data, annotation and predicted gene targets. miRBase takes over...
The miRBase database aims to provide integrated interfaces to comprehensive microRNA sequence data, annotation and predicted gene targets. miRBase takes over functionality from the microRNA Registry and fulfils three main roles: the miRBase Registry acts as an independent arbiter of microRNA gene nomenclature, assigning names prior to publication of novel miRNA sequences. miRBase Sequences is the primary online repository for miRNA sequence data and annotation. miRBase Targets is a comprehensive new database of predicted miRNA target genes. miRBase is available at http://microrna.sanger.ac.uk/.
Topics: Animals; Base Sequence; Databases, Nucleic Acid; Gene Expression Regulation; Internet; MicroRNAs; Registries; Terminology as Topic; User-Computer Interface
PubMed: 16381832
DOI: 10.1093/nar/gkj112 -
Molecular Cell Jun 20197-methylguanosine (m7G) is present at mRNA caps and at defined internal positions within tRNAs and rRNAs. However, its detection within low-abundance mRNAs and microRNAs...
7-methylguanosine (m7G) is present at mRNA caps and at defined internal positions within tRNAs and rRNAs. However, its detection within low-abundance mRNAs and microRNAs (miRNAs) has been hampered by a lack of sensitive detection strategies. Here, we adapt a chemical reactivity assay to detect internal m7G in miRNAs. Using this technique (Borohydride Reduction sequencing [BoRed-seq]) alongside RNA immunoprecipitation, we identify m7G within a subset of miRNAs that inhibit cell migration. We show that the METTL1 methyltransferase mediates m7G methylation within miRNAs and that this enzyme regulates cell migration via its catalytic activity. Using refined mass spectrometry methods, we map m7G to a single guanosine within the let-7e-5p miRNA. We show that METTL1-mediated methylation augments let-7 miRNA processing by disrupting an inhibitory secondary structure within the primary miRNA transcript (pri-miRNA). These results identify METTL1-dependent N7-methylation of guanosine as a new RNA modification pathway that regulates miRNA structure, biogenesis, and cell migration.
Topics: A549 Cells; Base Sequence; Biological Assay; Caco-2 Cells; Cell Movement; Cell Proliferation; Guanosine; HEK293 Cells; Humans; Methylation; Methyltransferases; MicroRNAs; Nucleic Acid Conformation; RNA Processing, Post-Transcriptional
PubMed: 31031083
DOI: 10.1016/j.molcel.2019.03.040 -
FEBS Letters Jun 2018MicroRNAs (miRNAs) are evolutionarily conserved small regulatory RNAs that participate in the adjustment of many, if not all, fundamental biological processes. Molecular... (Review)
Review
MicroRNAs (miRNAs) are evolutionarily conserved small regulatory RNAs that participate in the adjustment of many, if not all, fundamental biological processes. Molecular mechanisms involved in miRNA biogenesis and mode of action have been elucidated in the past two decades. Similar to many cellular pathways, miRNA processing and function can be globally or specifically regulated at several levels and by numerous proteins and RNAs. Given their role as fine-tuning molecules, it is essential for miRNA expression to be tightly regulated in order to maintain cellular homeostasis. Here, we review our current knowledge of the first step of their maturation occurring in the nucleus and how it can be specifically and dynamically modulated.
Topics: Animals; Cell Nucleus; Gene Expression Regulation; Homeostasis; Humans; MicroRNAs; Models, Molecular; RNA Polymerase II; Ribonuclease III
PubMed: 29683487
DOI: 10.1002/1873-3468.13067 -
Current Opinion in Structural Biology Oct 2022MicroRNAs are prevalent regulators of gene expression, controlling most of the proteome in multicellular organisms. To generate the functional small RNAs, precise... (Review)
Review
MicroRNAs are prevalent regulators of gene expression, controlling most of the proteome in multicellular organisms. To generate the functional small RNAs, precise processing steps are required. In animals, microRNA biogenesis is initiated by Microprocessor that minimally consists of the Drosha enzyme and its partner, DGCR8. This first step is critical for selecting primary microRNAs, and many RNA-binding proteins and regulatory pathways target both the accuracy and efficiency of microRNA maturation. Structures of Drosha and DGCR8 in complex with primary microRNAs elucidate how RNA structural features rather than sequence provide the framework for substrate recognition. Comparing multiple states of Microprocessor and the closely related Dicer homologs shed light on the dynamic protein-RNA complex assembly and disassembly required to recognize RNAs with diverse sequences via common structural features.
Topics: Animals; MicroRNAs; Proteome; RNA Processing, Post-Transcriptional; RNA-Binding Proteins
PubMed: 36067707
DOI: 10.1016/j.sbi.2022.102442 -
Balkan Medical Journal Feb 2020Cardiovascular diseases are one of the most common causes of death in both developing and developed countries worldwide. Even though there have been improvements in...
Cardiovascular diseases are one of the most common causes of death in both developing and developed countries worldwide. Even though there have been improvements in primary prevention, the prevalence of cardiovascular diseases continues to increase in recent years. Hence, it is crucial to both investigate the molecular pathophysiology of cardiovascular diseases in-depth and find novel biomarkers regarding the early and proper prevention and diagnosis of these diseases. MicroRNAs, or miRNAs, are endogenous, conserved, single-stranded non-coding RNAs of 21-25 nucleotides in length. miRNAs have important roles in various cellular events such as embryogenesis, proliferation, vasculogenesis, apoptosis, cell growth, differentiation, and tumorigenesis. They also have potential roles in the cardiovascular system, including angiogenesis, cardiac cell contractility, control of lipid metabolism, plaque formation, the arrangement of cardiac rhythm, and cardiac cell growth. Circulating miRNAs are promising novel biomarkers for purposes of the diagnosis and prognosis of cardiovascular diseases. Cell or tissue specificity, stability in serum or plasma, resistance to degradative factors such as freeze-thaw cycles or enzymes in the blood, and fast-release kinetics, provide the potential for miRNAs to be surrogate markers for the early and accurate diagnosis of disease and for predicting middle- or long-term prognosis. Moreover, it may be a logical approach to combine miRNAs with traditional biomarkers to improve risk stratification and long-term prognosis. In addition to their efficacy in both diagnosis and prognosis, miRNA-based therapeutics may be beneficial for treating cardiovascular diseases using novel platforms and computational tools and in combination with traditional methods of analysis. microRNAs are promising, novel therapeutic agents, which can affect multiple genes using different signaling pathways. miRNAs therapeutic modulation techniques have been used in the settings of atherosclerosis, acute myocardial infarction, restenosis, vascular remodeling, arrhythmias, hypertrophy and fibrosis, angiogenesis and cardiogenesis, aortic aneurysm, pulmonary hypertension, and ischemic injury. This review presents detailed information about miRNAs regarding structure and biogenesis, stages of synthesis and functions, expression profiles in serum/plasma of living organisms, diagnostic and prognostic potential as novel biomarkers, and therapeutic applications in various diseases.
Topics: Biomarkers; Cardiovascular Diseases; Humans; MicroRNAs; Prognosis
PubMed: 32018347
DOI: 10.4274/balkanmedj.galenos.2020.2020.1.94 -
Cells Jan 2023MicroRNAs (miRNAs) are versatile, post-transcriptional regulators of gene expression. Canonical miRNAs are generated through the two-step DROSHA- and DICER-mediated... (Review)
Review
MicroRNAs (miRNAs) are versatile, post-transcriptional regulators of gene expression. Canonical miRNAs are generated through the two-step DROSHA- and DICER-mediated processing of primary miRNA (pri-miRNA) transcripts with optimal or suboptimal features for DROSHA and DICER cleavage and loading into Argonaute (AGO) proteins, whereas multiple hairpin-structured RNAs are encoded in the genome and could be a source of non-canonical miRNAs. Recent advances in miRNA biogenesis research have revealed details of the structural basis of miRNA processing and cluster assistance mechanisms that facilitate the processing of suboptimal hairpins encoded together with optimal hairpins in polycistronic pri-miRNAs. In addition, a deeper investigation of miRNA-target interaction has provided insights into the complexity of target recognition with distinct outcomes, including target-mediated miRNA degradation (TDMD) and cooperation in target regulation by multiple miRNAs. Therefore, the coordinated or network regulation of both miRNA biogenesis and miRNA-target interaction is prevalent in miRNA biology. Alongside recent advances in the mechanistic investigation of miRNA functions, this review summarizes recent findings regarding the ordered regulation of miRNA biogenesis and miRNA-target interaction.
Topics: MicroRNAs; RNA Processing, Post-Transcriptional
PubMed: 36672241
DOI: 10.3390/cells12020306