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Results for “MicroRNA, (miRNA)”

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PubMed2004

MicroRNA-196 inhibits HOXB8 expression in myeloid differentiation of HL60 cells.

MicroRNAs (miRNAs) are endogenous small RNAs (approximately 21-25 nts) that can regulate gene expression at a post-transcriptional level. Recently a large number of miRNAs have been identified from plants and animals. In addition, it has been reported that these small RNAs can participate in cell differentiation of developmental timing. In this study, we show that microRNA-196 (miR-196) inhibits HOXB8 expression in myeloid differentiation of HL 60 cells. MiR-196 has perfect complementarity with target sequence of 3'-UTR in HOXB8 mRNA. Exogenous expressed miR-196 repressed expression of HOXB8 via cleaving mRNAs. Moreover miR-196 enhanced myeloid differentiation of HL60 cells. These results suggest that miR-196 participates in myeloid differentiation of HL60 cells via regulation of HOXB8 expression.

Base Sequence↗

PubMed2004

MicroRNAs: something important between the genes.

Non-coding small endogenous RNAs, of 21-24 nucleotides in length, have recently emerged as important regulators of gene expression in both plants and animals. At least three categories of small RNAs exist in plants: short interfering RNAs (siRNAs) deriving from viruses or transgenes and mediating virus resistance or transgene silencing via RNA degradation; siRNAs deriving from transposons or transgene promoters and controlling transposon and transgene silencing probably via chromatin changes; and microRNAs (miRNAs) deriving from intergenic regions of the genome and regulating the expression of endogenous genes either by mRNA cleavage or translational repression. The disruption of miRNA-mediated regulation causes developmental abnormalities in plants, demonstrating that miRNAs play an important role in the regulation of developmental decisions.

Gene Expression Regulation, Plant↗

PubMed2006

MicroRNA expression profiling of single whole embryonic stem cells.

MicroRNAs (miRNAs) are a class of 17-25 nt non-coding RNAs that have been shown to have critical functions in a wide variety of biological processes during development. Recently developed miRNA microarray techniques have helped to accelerate research on miRNAs. However, in some instances there is only a limited amount of material available for analysis, which requires more sensitive techniques that can preferably work on single cells. Here we demonstrate that it is possible to analyse miRNA in single cells by using a real-time PCR-based 220-plex miRNA expression profiling method. Development of this technique will greatly facilitate miRNA-related research on cells, such as the founder population of primordial germ cells where rapid and dynamic changes occur in a few cells, and for analysing heterogeneous population of cells. In these and similar cases, our method of single cell analysis is critical for elucidating the diverse roles of miRNAs.

Animals↗

PubMed2006

MicroRNA: biogenetic and functional mechanisms and involvements in cell differentiation and cancer.

MicroRNAs (miRNAs) are endogenous small noncoding RNAs (20-23 nucleotides) that negatively regulate the gene expressions at the posttranscriptional level by base pairing to the 3' untranslated region of target messenger RNAs. Hundreds of miRNAs have been identified in humans and evolutionarily conserved from plants to animals. It is revealed that miRNAs regulate various physiological and pathological pathways such as cell differentiation, cell proliferation, and tumoriogenesis. By the computational analysis, it is predicted that 30% of protein-encoding genes are regulated by miRNAs. In this review, we discuss recent remarkable advances in the miRNA biogenetic and functional mechanisms and the involvements of miRNAs in cell differentiation, especially in hematopoietic lineages, and cancer. These evidences offer the possibility that miRNAs would be potentially useful for drug discovery.

Animals↗

PubMed2006

MicroRNAs in human immunodeficiency virus-1 infection.

Initially reported for Caenorhabditis elegans, microRNA (miRNA) has been shown to regulate gene expression in plants, flies, and mammals . Here, we report on our approaches to investigate the role of miRNAs in human immunodeficiency virus (HIV)-1 infection. Using computer-directed foldings, we first identify potential sequences in HIV-1 that putatively encode miRNAs. Subsequently, we use Northern blotting of RNAs isolated from HIV-infected cells to confirm expression of predicted miRNA sequences. Finally, we use a scanning algorithm to search 3' untranslated regions (UTRs) of human messenger RNAs (mRNAs) in the attempt to predict potential sites targeted by HIV-1 miRNAs.

Algorithms↗

PubMed2006

MicroRNA biogenesis: isolation and characterization of the microprocessor complex.

The recently discovered microRNAs (miRNAs) are a large family of small regulatory RNAs that have been implicated in controlling diverse pathways in a variety of organisms (1, 2). For posttranscriptional gene silencing, one strand of the miRNA is used to guide components of the RNA interference machinery, including Argonaute 2, to messenger RNAs (mRNAs) with complementary sequences (3, 4). Thus, targeted mRNAs are either cleaved by the endonuclease Argonaute 2 (5, 6), or protein synthesis is blocked by an as yet uncharacterized mechanism (7, 8). Genes encoding miRNAs are transcribed as long primary miRNAs (pri-miRNAs) that are sequentially processed by components of the nucleus and cytoplasm to yield a mature, approx 22-nucleotide (nt)-long miRNA (9). Two members of the ribonuclease (RNase) III endonuclease protein family, Drosha and Dicer, have been implicated in this two-step processing (10-13). To further our understanding of miRNA biogenesis and function it will be essential to identify the protein complexes involved. We were interested in defining the proteins required for the initial nuclear processing of pri-miRNAs to the approx 60- to 70-nt stem-loop intermediates known as precursor miRNAs (pre-miRNAs) (9, 10). This led to our identification of a protein complex we termed Microprocessor, which is necessary and sufficient for processing pri-miRNA to premiRNAs (14). The Microprocessor complex comprises Drosha and the double-stranded RNAbinding protein DiGeorge syndrome critical region 8 gene (DGCR8), which is deleted in DiGeorge syndrome (15, 16). In this chapter, we detail the methods used for the biochemical isolation and identification of the Microprocessor complex from human cells. We include a protocol for the in vitro analysis of pri-miRNA processing activity of the purified Microprocessor complex.

Cell Line↗

PubMed2006

MicroRNAs: small but potent oncogenes or tumor suppressors.

MicroRNAs (miRNAs) are small, non-coding RNAs that modulate the expression of target mRNA. Many miRNAs are known to be up- or downregulated in a variety of cancers, suggesting a role for miRNAs in tumorigenesis. The correlation between the expression of miRNAs and their effects on target oncogenes, on tumorigenesis and on the proliferation of cancer cells is beginning to gain experimental evidence. For example, the miRNA (miR)-17-92 cluster has been characterized as an oncogene, while let-7 represses Ras and miR-15a/-16-1 represses Bcl-2, thereby acting as tumor suppressors. Thus, an oncogenic or tumor suppressive miRNA may have potential as a therapeutic target to control cancers. This review will discuss the relationship between miRNAs and tumorigenesis, and the potential for modulating miRNAs for the treatment of cancer.

Animals↗

PubMed2024

Suppression of CNS APOE4 Expression by miRNAs Delivered by the S2 AAVrh.10 Capsid-Modified AAV Vector.

The homozygous Apolipoprotein E (APOE4) genotype is the major risk factor for the development of early Alzheimer's disease. Genome engineering studies in mouse models of human APOE4-dependent pathology have established that reduction of APOE4 expression can rescue the phenotype. We hypothesized that APOE4 could be suppressed in the CNS of APOE4 homozygotes using adeno-associated virus (AAV) expression of microRNAs (miRNA) designed to hybridize to APOE mRNA. We screened nine different miRNAs targeting APOE following transfection in HEK293T and Huh7 cells. Optimal APOE suppression was obtained with mir2A (targeting coding region nt330-351) and mirN4 (3' untranslated region nt1142-1162). miRNA expression cassettes were designed with two copies of each of these two miRNAs co-expressed with a mCherry transgene. To optimize delivery of these miRNAs, an engineered AAVrh.10 variant was identified from a screen of multiple peptide insertions into capsid loop IV and substitutions in loop VIII. This led to identifying the AAV.S2 capsid with enhanced transduction of both neurons and glia and enhanced distribution in the brain. The engineered capsid was used to deliver the APOE miRNA suppression cassette to the hippocampus of TRE4 mice (human APOE4 knock-in replacement of the murine apoE locus). Two weeks after intra-hippocampus administration, regional expression of miRNA at the injection site was quantified at the mRNA level relative to an endogenous reference. The AAV.S2 capsid provided 2.31 ± 0.37-fold higher expression of miRNA over that provided by AAVrh.10 (p < 0.05). In the targeted region, a single intra-hippocampus AAV.S2 administration suppressed hippocampal APOE4 mRNA levels by 76.5 ± 3.9% compared with 41.3 ± 3.3% with the same cassette delivered by the wildtype AAVrh.10 capsid (p < 0.0001). We conclude that an expression cassette with two different miRNAs targeting APOE4 delivered by the AAV.S2 capsid will generate highly significant suppression of APOE4 in the CNS.

Dependovirus↗

PubMed2025

Hepatocyte-Enriched miRNA-193b-3p Promotes Hepatitis B Virus Replication by Dual Activation of Viral Core Promoter Activity and Autophagy Induction by Targeting IGF-1R.

Hepatitis B virus (HBV) infection is a principal cause of severe liver disease in humans and is associated with increased levels of specific serum or intracellular microRNAs (miRNAs). Among these, miR-193b-3p is a liver-enriched miRNA; however, its role in HBV replication remains unknown. This study aimed to investigate the influence of chronic HBV infection on miR-193b-3p levels in the peripheral blood and liver tissues of patients with chronic hepatitis B (CHB), evaluate the effect of miR-193b-3p on HBV replication both in vitro and in vivo, and elucidate the potential underlying mechanisms. We showed that hepatic miR-193b-3p levels in patients with CHB were significantly elevated compared with those in healthy controls. Ectopic expression of miR-193b-3p significantly enhanced HBV replication and transcription in different hepatoma cell lines. Furthermore, we identified IGF-1R as a direct target through which miR-193b-3p regulates HBV replication. Mechanistically, miR-193b-3p increased HBV core promoter activity via the IGF-1R/FXRα axis, thereby enhancing HBV transcription. Additionally, miR-193b-3p increased IGF-1R/Akt/MDM2/p53 signaling-mediated autophagy induction, which in turn facilitated increased HBV post-transcriptional activity. Collectively, hepatocyte-enriched miR-193b-3p exerts a proviral effect on HBV replication through dual synergistic mechanisms, offering novel insights into its role in HBV replication and potential therapeutic implications in CHB infection.

Humans↗

PubMed2005

New perspectives on neoplasia and the RNA world.

Key tenets of modern biology are the central place of protein in cell regulation and the flow of genetic information from DNA to RNA to protein. However, it is becoming increasingly apparent that genomes are much more complex than hitherto thought with remarkably complex regulatory systems. The notion that the fraction of the genome involved in coding protein is all that matters is increasingly being questioned as the roles of non-coding RNA (ncRNA) in cellular systems becomes recognised. The RNA world, including microRNA (miRNA), small inhibitory RNA (siRNA) and other RNA species, are now recognised as being crucial for the regulation of chromatin structure, gene expression, mRNA processing and splicing, mRNA stability and translational control. Furthermore such ncRNA systems may be perturbed in disease states and most notably in neoplasia, including in haematological malignancies. Here the burgeoning evidence for a role of miRNA in neoplasia is reviewed and the importance of understanding the RNA world emphasised.

Alternative Splicing↗

PubMed2026

Design, expression, purification, and application of novel recombinant miR-491 molecules to define the biogenesis and function of miR-491-3p versus -5p in posttranscriptional regulation of UDP-glucuronosyltransferase 1A1.

Interindividual variations in drug metabolism involve various factors, including posttranscriptional gene regulation mechanisms controlled by microRNAs (miRNAs or miRs) derived from the genome. The aim of this study was to use RNA bioengineering technology to produce novel recombinant human miR-491-5p, miR-491-3p, and pre-miR-491 molecules, namely BioRNA/miR-491-5p, BioRNA/miR-491-3p, and BioRNA/pre-miR-491, respectively, and define their functional difference in regulating UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and drug-metabolizing capacity. All 6 BioRNAs were heterologously overexpressed in Escherichia coli (>30% of total RNA) and isolated by fast protein liquid chromatography to high purity (>97%). As BioRNA/pre-miR-491 agents were processed to both 5p and 3p strands in Hep3B and HepG2 cells, BioRNA/miR-491-5p and -3p were selectively processed to 5p and 3p, respectively, and each accumulated to greater levels. Immunoblotting and immunofluorescence studies demonstrated the efficacy of BioRNA/miR-491-3p to suppress UGT1A1 protein levels in Hep3B and HepG2 cells, localized on the endoplasmic reticulum, exhibiting monomeric (∼55 kDa) and oligomeric (∼150 kDa) bands under different conditions, whereas BioRNA/pre-miR-491 and miR-491-5p had no effects. Using a fluorescent substrate, N-butyl-4-(4-hydroxyphenyl)-1,8-naphthalimide, lower UGT1A1 drug-metabolizing capacities were found in cells treated with BioRNA/miR-491-3p. In addition, liquid chromatography-tandem mass spectrometry analysis revealed a 45% reduction of estradiol 3-glucuronidation activity by BioRNA/miR-491-3p in Hep3B cells, whereas formation of estradiol 17-glucuronidation mediated by other UGTs was unchanged. Together, these results underline the role of miR-491-3p in regulating UGT1A1 and its impact on cellular drug-metabolizing capacity while demonstrating the applications of recombinant miRNA agents to delineating the importance of posttranscriptional gene regulation in drug metabolism. SIGNIFICANT STATEMENT: Research on posttranscriptional gene regulation mainly uses miRNA mimics chemically synthesized in vitro. This study successfully produced 6 novel recombinant miR-491 molecules through in vivo fermentation with transfer RNA scaffold and transfer RNA-fused pre-miRNA carrier-based technologies, which were further utilized to delineate the biogenesis and function of miR-491-3p versus -5p in modulating UDP-glucuronosyltransferase 1A1 protein levels and drug-metabolizing capacity. The findings demonstrate the role of miR-491-3p in regulating UDP-glucuronosyltransferase 1A1 and value of recombinant miRNA agents for studying drug metabolism.

Humans↗

PubMed2006

Strategies to determine the biological function of microRNAs.

MicroRNAs (miRNAs) are regulators of gene expression that control many biological processes in development, differentiation, growth and metabolism. Their expression levels, small size, abundance of repetitive copies in the genome and mode of action pose unique challenges in studies elucidating the function of miRNAs. New technologies for identification, expression profiling and target gene validation, as well as manipulation of miRNA expression in vivo, will facilitate the study of their contribution to biological processes and disease. Such information will be crucial to exploit the emerging knowledge of miRNAs for the development of new human therapeutic applications.

Animals↗

PubMed2005

MicroRNA biogenesis: coordinated cropping and dicing.

The recent discovery of microRNAs (miRNAs) took many by surprise because of their unorthodox features and widespread functions. These tiny, approximately 22-nucleotide, RNAs control several pathways including developmental timing, haematopoiesis, organogenesis, apoptosis, cell proliferation and possibly even tumorigenesis. Among the most pressing questions regarding this unusual class of regulatory miRNA-encoding genes is how miRNAs are produced in cells and how the genes themselves are controlled by various regulatory networks.

Animals↗

PubMed2006

Evidence that microRNAs are associated with translating messenger RNAs in human cells.

MicroRNAs (miRNAs) regulate gene expression post-transcriptionally by binding the 3' untranslated regions of target mRNAs. We examined the subcellular distribution of three miRNAs in exponentially growing HeLa cells and found that the vast majority are associated with mRNAs in polysomes. Several lines of evidence indicate that most of these mRNAs, including a known miRNA-regulated target (KRAS mRNA), are actively being translated.

Cytoplasm↗

PubMed2002

MicroRNA maturation: stepwise processing and subcellular localization.

MicroRNAs (miRNAs) constitute a novel, phylogenetically extensive family of small RNAs ( approximately 22 nucleotides) with potential roles in gene regulation. Apart from the finding that miRNAs are produced by Dicer from the precursors of approximately 70 nucleotides (pre-miRNAs), little is known about miRNA biogenesis. Some miRNA genes have been found in close conjunction, suggesting that they are expressed as single transcriptional units. Here, we present in vivo and in vitro evidence that these clustered miRNAs are expressed polycistronically and are processed through at least two sequential steps: (i) generation of the approximately 70 nucleotide pre-miRNAs from the longer transcripts (termed pri-miRNAs); and (ii) processing of pre-miRNAs into mature miRNAs. Subcellular localization studies showed that the first and second steps are compartmentalized into the nucleus and cytoplasm, respectively, and that the pre-miRNA serves as the substrate for nuclear export. Our study suggests that the regulation of miRNA expression may occur at multiple levels, including the two processing steps and the nuclear export step. These data will provide a framework for further studies on miRNA biogenesis.

Biological Transport↗

PubMed2005

MicroRNA-directed regulation of Arabidopsis AUXIN RESPONSE FACTOR17 is essential for proper development and modulates expression of early auxin response genes.

The phytohormone auxin plays critical roles during plant growth, many of which are mediated by the auxin response transcription factor (ARF) family. MicroRNAs (miRNAs), endogenous 21-nucleotide riboregulators, target several mRNAs implicated in auxin responses. miR160 targets ARF10, ARF16, and ARF17, three of the 23 Arabidopsis thaliana ARF genes. Here, we describe roles of miR160-directed ARF17 posttranscriptional regulation. Plants expressing a miRNA-resistant version of ARF17 have increased ARF17 mRNA levels and altered accumulation of auxin-inducible GH3-like mRNAs, YDK1/GH3.2, GH3.3, GH3.5, and DFL1/GH3.6, which encode auxin-conjugating proteins. These expression changes correlate with dramatic developmental defects, including embryo and emerging leaf symmetry anomalies, leaf shape defects, premature inflorescence development, altered phyllotaxy along the stem, reduced petal size, abnormal stamens, sterility, and root growth defects. These defects demonstrate the importance of miR160-directed ARF17 regulation and implicate ARF17 as a regulator of GH3-like early auxin response genes. Many of these defects resemble phenotypes previously observed in plants expressing viral suppressors of RNA silencing and plants with mutations in genes important for miRNA biogenesis or function, providing a molecular rationale for phenotypes previously associated with more general disruptions of miRNA function.

Arabidopsis↗

PubMed2006

SAGE detects microRNA precursors.

BACKGROUND: MicroRNAs (miRNAs) have been shown to play important roles in regulating gene expression. Since miRNAs are often evolutionarily conserved and their precursors can be folded into stem-loop hairpins, many miRNAs have been predicted. Yet experimental confirmation is difficult since miRNA expression is often specific to particular tissues and developmental stages. RESULTS: Analysis of 29 human and 230 mouse longSAGE libraries revealed the expression of 22 known and 10 predicted mammalian miRNAs. Most were detected in embryonic tissues. Four SAGE tags detected in human embryonic stem cells specifically match a cluster of four human miRNAs (mir-302a, b, c&d) known to be expressed in embryonic stem cells. LongSAGE data also suggest the existence of a mouse homolog of human and rat mir-493. CONCLUSION: The observation that some orphan longSAGE tags uniquely match miRNA precursors provides information about the expression of some known and predicted miRNAs.

Animals↗

PubMed2006

A plant miRNA contributes to antibacterial resistance by repressing auxin signaling.

Plants and animals activate defenses after perceiving pathogen-associated molecular patterns (PAMPs) such as bacterial flagellin. In Arabidopsis, perception of flagellin increases resistance to the bacterium Pseudomonas syringae, although the molecular mechanisms involved remain elusive. Here, we show that a flagellin-derived peptide induces a plant microRNA (miRNA) that negatively regulates messenger RNAs for the F-box auxin receptors TIR1, AFB2, and AFB3. Repression of auxin signaling restricts P. syringae growth, implicating auxin in disease susceptibility and miRNA-mediated suppression of auxin signaling in resistance.

Arabidopsis↗