Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “microRNA expression”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,153 records · Page 64Linked to original sources
PubMed2005

A herpes simplex virus type 1 mutant expressing a baculovirus inhibitor of apoptosis gene in place of latency-associated transcript has a wild-type reactivation phenotype in the mouse.

The latency-associated transcript (LAT) is essential for the wild-type herpes simplex virus type 1 (HSV-1) high-reactivation phenotype since LAT- mutants have a low-reactivation phenotype. We previously reported that LAT can decrease apoptosis and proposed that this activity is involved in LAT's ability to enhance the HSV-1 reactivation phenotype. The first 20% of the primary 8.3-kb LAT transcript is sufficient for enhancing the reactivation phenotype and for decreasing apoptosis, supporting this proposal. For this study, we constructed an HSV-1 LAT- mutant that expresses the baculovirus antiapoptosis gene product cpIAP under control of the LAT promoter and in place of the LAT region mentioned above. Mice were ocularly infected with this mutant, designated dLAT-cpIAP, and the reactivation phenotype was determined using the trigeminal ganglion explant model. dLAT-cpIAP had a reactivation phenotype similar to that of wild-type virus and significantly higher than that of (i) the LAT- mutant dLAT2903; (ii) dLAT1.5, a control virus containing the same LAT deletion as dLAT-cpIAP, but with no insertion of foreign DNA, thereby controlling for potential readthrough transcription past the cpIAP insert; and (iii) dLAT-EGFP, a control virus identical to dLAT-cpIAP except that it contained the enhanced green fluorescent protein open reading frame (ORF) in place of the cpIAP ORF, thereby controlling for expression of a random foreign gene instead of the cpIAP gene. These results show that an antiapoptosis gene with no sequence similarity to LAT can efficiently substitute for the LAT function involved in enhancing the in vitro-induced HSV-1 reactivation phenotype in the mouse.

Animals↗
PubMed2004

The C. elegans Polycomb gene SOP-2 encodes an RNA binding protein.

Epigenetic silencing of Hox cluster genes by Polycomb group (PcG) proteins is thought to involve the formation of a stably inherited repressive chromatin structure. Here we show that the C. elegans-specific PcG protein SOP-2 directly binds to RNA through three nonoverlapping regions, each of which is essential for its localization to characteristic nuclear bodies and for its in vivo function in the repression of Hox genes. Functional studies indicate that the RNA involved in SOP-2 binding is distinct from either siRNA or microRNA. Remarkably, the vertebrate PcG protein Rae28, which is functionally and structurally related to SOP-2, also binds to RNA through an FCS finger domain. Substitution of the Rae28 FCS finger for the essential RNA binding region of SOP-2 partially restores localization to nuclear bodies. These observations suggest that direct binding to RNA is an evolutionarily conserved and potentially important property of PcG proteins.

Animals↗
PubMed2025

The pathway of autophagy in the epigenetic landscape of Mycobacterium-host interactions.

Macroautophagy (autophagy) is an evolutionarily conserved process that degrades excess cytoplasmic components, such as protein aggregates and damaged organelles, by encapsulating them within double-membrane autophagosomes. These autophagosomes undergo distinct stages - initiation, phagophore nucleation, expansion, and closure - before fusing with lysosomes (or occasionally endosomes) for degradation and recycling. This process is regulated by ATG (autophagy related) proteins, which govern autophagosome formation and lysosomal fusion. Epigenetic modifications and transcription factors can regulate ATG gene expression in the nucleus. Autophagy also plays a key role in eliminating intracellular Mycobacterium tuberculosis (Mtb) through the lytic and antimicrobial activities of autolysosomes, which are more potent antimicrobial compartments than conventional phagosomes. Emerging evidence suggests that Mtb can modify the host epigenome and transcriptional machinery, significantly affecting the host immune response. This review explores the epigenetic regulation of autophagy during mycobacterium-host interactions. The interplay between epigenetic regulation and autophagy highlights a crucial aspect of host-pathogen interactions during Mtb infection. Understanding how Mtb manipulates the host epigenome to regulate autophagy could lead to the development of novel therapeutic strategies that enhance autophagic pathways or counteract Mtb's immune evasion tactics.Abbreviations: AM: Alveolar macrophages; ATG: autophagy related; DNMT: DNA methyltransferase; FOXO3: forkhead box O3; HAT: histone acetyltransferase; HDAC: histone deacetylase; MIR: microRNA; MTOR: mechanistic target of rapamycin kinase; Mtb: Mycobacterium tuberculosis; ROS: reactive oxygen species; SIRT: sirtuin; STPK: serine/threonine protein kinase.

Autophagy↗
PubMed2005

RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus.

The Dlk1-Gtl2 imprinted domain, encompassing the callipyge (CLPG) locus in sheep, has recently been shown to harbor a large number of maternally expressed miRNA genes [1, 2]. Two of these (mir127 and mir136) are processed from a transcript (antiPeg11) that is antisense to Rtl1/Peg11, a paternally expressed intronless gene with homology to the gag and pol polyproteins of Sushi-like retroelements [3]. We herein demonstrate that several additional miRNAs are processed from antiPeg11 and that these regulate Rtl1/Peg11 in trans by guiding RISC-mediated cleavage of its mRNA. This is the first demonstration of miRNA-mediated RNAi involving imprinted genes in mammals.

Animals↗
PubMed2006

Overlapping functions of argonaute proteins in patterning and morphogenesis of Drosophila embryos.

Argonaute proteins are essential components of the molecular machinery that drives RNA silencing. In Drosophila, different members of the Argonaute family of proteins have been assigned to distinct RNA silencing pathways. While Ago1 is required for microRNA function, Ago2 is a crucial component of the RNA-induced silencing complex in siRNA-triggered RNA interference. Drosophila Ago2 contains an unusual amino-terminus with two types of imperfect glutamine-rich repeats (GRRs) of unknown function. Here we show that the GRRs of Ago2 are essential for the normal function of the protein. Alleles with reduced numbers of GRRs cause specific disruptions in two morphogenetic processes associated with the midblastula transition: membrane growth and microtubule-based organelle transport. These defects do not appear to result from disruption of siRNA-dependent processes but rather suggest an interference of the mutant Ago2 proteins in an Ago1-dependent pathway. Using loss-of-function alleles, we further demonstrate that Ago1 and Ago2 act in a partially redundant manner to control the expression of the segment-polarity gene wingless in the early embryo. Our findings argue against a strict separation of Ago1 and Ago2 functions and suggest that these proteins act in concert to control key steps of the midblastula transition and of segmental patterning.

Animals↗
PubMedDate not supplied

The RNA binding protein FMRP: new connections and missing links.

The loss of the fragile X mental retardation protein (FMRP) is responsible for the most common cause of inherited mental retardation called the fragile X syndrome. FMRP is suspected to participate in the synaptic plasticity of neurons by acting on posttranscriptional control of gene expression. FMRP is an RNA binding protein that associates with mRNAs together with other proteins to form large ribonucleoprotein complexes. These complexes are proposed to participate in the transport, localization and translation of target mRNAs. Progress has been made recently in the identification of the mRNAs and the proteins present in these complexes and a possible connection with the micro-RNA dependent regulatory pathway has been established.

Female↗
PubMed2005

A screen for conserved sequences with biased base composition identifies noncoding RNAs in the A-T rich genome of Plasmodium falciparum.

Noncoding RNAs (ncRNAs) such as snRNAs, snoRNAs and microRNAs play important roles in transcription and translation control. These ncRNAs have yet to be discovered in the malarial parasite Plasmodium falciparum, an organism in which these basic biological processes are poorly understood. Inspired by a report by Klein et al., we initiated a bioinformatics screen to uncover several candidate ncRNAs from the parasite genome using two simple criteria: first, elevated GC content in the highly A-T rich intergenic regions of the P. falciparum genome and second, conservation of sequence homology between malaria parasite species. We show that all the annotated tRNAs can be successfully identified in our screen as well as several new candidates that show homology to snRNAs and snoRNAs, and ten candidate ncRNAs of unknown function. Three of the candidate snRNAs, a predicted selenocysteine tRNA and two candidates of unknown function are expressed in asexual stage parasites, further validating the screen. With these results, the biological processes underlying RNA-mediated regulation of transcription, translation and splicing can be studied in an important human pathogen.

Animals↗
PubMed2006

A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors.

Endogenous small RNAs (miRNAs) regulate gene expression by mechanisms conserved across metazoans. While the number of verified human miRNAs is still expanding, only few have been functionally annotated. To perform genetic screens for novel functions of miRNAs, we developed a library of vectors expressing the majority of cloned human miRNAs and created corresponding DNA barcode arrays. In a screen for miRNAs that cooperate with oncogenes in cellular transformation, we identified miR-372 and miR-373, each permitting proliferation and tumorigenesis of primary human cells that harbor both oncogenic RAS and active wild-type p53. These miRNAs neutralize p53-mediated CDK inhibition, possibly through direct inhibition of the expression of the tumor-suppressor LATS2. We provide evidence that these miRNAs are potential novel oncogenes participating in the development of human testicular germ cell tumors by numbing the p53 pathway, thus allowing tumorigenic growth in the presence of wild-type p53.

Cells, Cultured↗
PubMed2006

Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer.

Common fragile sites (CFSs) are regions of chromosomal break that may play a role in oncogenesis. The most frequent alteration occurs at FRA3B, within the FHIT gene, at chromosomal region 3p14. We studied a series of breast carcinomas for break of a CFS at 6q26, FRA6E, and its associated gene PARK2, using fluorescence in situ hybridization on tissue microarrays (TMA). We found break of PARK2 in 6% of cases. We studied the PARK2-encoded protein Parkin by using immunohistochemistry on the same TMA. Loss of Parkin was found in 13% of samples but was not correlated with PARK2 break. PARK2 break but not Parkin expression was correlated with prognosis. Alteration of PARK2/FRA6E may cause haplo-insufficiency of one or several telomeric potential tumor suppressor genes (TSG). The AF-6/MLLT4 gene, telomeric of PARK2, encodes the Afadin scaffold protein, which is essential for epithelial integrity. Loss of Afadin was found in 14.5% of cases, and 36% of these cases showed PARK2 break. Loss of Afadin had prognostic impact, suggesting that AF-6 may be a TSG. Loss of Afadin was correlated with loss of FHIT expression, suggesting fragility of FRA6E and FRA3B in a certain proportion of breast tumors.

Acid Anhydride Hydrolases↗
PubMed2002

A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins.

Fragile X syndrome is a common form of inherited mental retardation caused by the loss of FMR1 expression. The FMR1 gene encodes an RNA-binding protein that associates with translating ribosomes and acts as a negative translational regulator. In Drosophila, the fly homolog of the FMR1 protein (dFMR1) binds to and represses the translation of an mRNA encoding of the microtuble-associated protein Futsch. We have isolated a dFMR1-associated complex that includes two ribosomal proteins, L5 and L11, along with 5S RNA. The dFMR1 complex also contains Argonaute2 (AGO2) and a Drosophila homolog of p68 RNA helicase (Dmp68). AGO2 is an essential component for the RNA-induced silencing complex (RISC), a sequence-specific nuclease complex that mediates RNA interference (RNAi) in Drosophila. We show that Dmp68 is also required for efficient RNAi. We further show that dFMR1 is associated with Dicer, another essential component of the RNAi pathway, and microRNAs (miRNAs) in vivo, suggesting that dFMR1 is part of the RNAi-related apparatus. Our findings suggest a model in which the RNAi and dFMR1-mediated translational control pathways intersect in Drosophila. Our findings also raise the possibility that defects in an RNAi-related machinery may cause human disease.

Amino Acid Sequence↗
PubMed2026

PCBP2 facilitates miR-93-5p-mediated repression of GDF11 in HCC cell lines.

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β superfamily, functions in skeletal muscle and neuronal regeneration and has been implicated in tumor suppression. In hepatocellular carcinoma (HCC), GDF11 expression is markedly downregulated, but the mechanisms responsible for this repression remain unclear. In this study, we examined whether the oncogenic miR-106b-25 cluster contributes to GDF11 suppression in HCC. We found that this cluster decreases GDF11 expression at both the mRNA and protein levels, with miR-93-5p acting as the dominant regulator. Inhibition of miR-93-5p with antisense oligonucleotides restored GDF11 expression and reduced HCC cell proliferation, migration, and invasion. Mechanistically, we identified the RNA-binding protein (RBP) PCBP2 as a key facilitator of miR-93-5p targeting of GDF11. PCBP2 binds a C-rich element adjacent to the miR-93-5p target site in the GDF11 3' UTR, thereby enhancing miR-93-5p-mediated repression. PCBP2 knockout attenuated miR-93-5p-mediated repression, whereas re-expression of PCBP2 restored it, supporting its modulatory role. Collectively, these findings identify PCBP2 as a modulator of miR-93-5p-mediated GDF11 repression and suggest that this regulatory interaction contributes to HCC cell proliferation, migration, and invasion. This work provides insights into the post-transcriptional control of the tumor suppressor and highlights the therapeutic potential of targeting miRNA-RBP interactions.

GDF11↗
PubMed2014

Jarid2 is induced by TCR signalling and controls iNKT cell maturation.

Jarid2 is a reported component of three lysine methyltransferase complexes, polycomb repressive complex 2 (PRC2) that methylates histone 3 lysine 27 (H3K27), and GLP-G9a and SETDB1 complexes that methylate H3K9. Here we show that Jarid2 is upregulated upon TCR stimulation and during positive selection in the thymus. Mice lacking Jarid2 in T cells display an increase in the frequency of IL-4-producing promyelocytic leukemia zinc finger (PLZF)(hi) immature invariant natural killer T (iNKT) cells and innate-like CD8(+) cells; Itk-deficient mice, which have a similar increase of innate-like CD8(+) cells, show blunted upregulation of Jarid2 during positive selection. Jarid2 binds to the Zbtb16 locus, which encodes PLZF, and thymocytes lacking Jarid2 show increased PLZF and decreased H3K9me3 levels. Jarid2-deficient iNKT cells perturb Th17 differentiation, leading to reduced Th17-driven autoimmune pathology. Our results establish Jarid2 as a novel player in iNKT cell maturation that regulates PLZF expression by modulating H3K9 methylation.

Animals↗
PubMed2026

The SPL-family transcription factor MpSPL3 orchestrates the proper regulation of vegetative and reproductive programs in Marchantia polymorpha.

SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) genes encode plant-specific transcription factors that are widely distributed across the plant kingdom. In angiosperms, the multimember SPL family regulates various biological processes, including vegetative-to-reproductive phase transition, inflorescence architecture, and lateral organ development. In contrast, the liverwort Marchantia polymorpha genome encodes only four SPL genes, with functional studies available only for microRNA-targeted members, MpSPL1 and MpSPL2. MpSPL1 was shown to control the meristem dormancy to modulate the thallus architecture, whereas MpSPL2 was found to promote the transition from vegetative-to-reproductive phase. Here, we investigate the impact of the MpSPL3 gene on M. polymorpha development. We demonstrate that MpSPL3 influences coordination of the vegetative growth and the reproductive phase transition. Knockout of MpSPL3 leads to strong growth retardation with disordered thallus morphology, reduced gemma cup number, and, most strikingly, complete loss of gametangiophore formation. Interestingly, overexpression of MpSPL3.2, the shorter isoform, has no detectable morphological effect, whereas the overexpression of MpSPL3.1, the longer isoform encoding a protein with an additional 61-aa long fragment, results in a delay in timing and reduced efficiency of gametangiophore production. Moreover, all the observed developmental abnormalities might be a consequence of the altered expression of genes essential for proper vegetative development and responsible for germ cell specification in MpSPL3 knockout and overexpression plants. Altogether, our findings demonstrate that MpSPL3 is important in regulating gametophyte development and ensuring reproductive success in M. polymorpha.

Marchantia↗
PubMed2005

Silence of the transcripts: RNA interference in medicine.

Silencing of gene expression by ribonucleic acid (RNA), known as RNA interference (RNAi), is now recognized as a major means of gene regulation in biology. In this mechanism, small noncoding double-stranded RNA molecules knock down gene expression through a variety of mechanisms that include messenger RNA (mRNA) degradation, inhibition of mRNA translation, or chromatin remodeling. The posttranscriptional mechanism of RNAi has been embraced by researchers as a powerful tool for generating deficient phenotypes without mutating the gene. In parallel, exciting recent results have promised its application in disease therapy. This review aims to summarize the current knowledge in this area and provide a roadmap that may eventually launch RNAi from the research bench to the medicine chest.

Animals↗
PubMed2006

The imprinted mouse Igf2r/Air cluster--a model maternal imprinting system.

Every diploid organism inherits a complete chromosome set from its father and mother in addition to the sex chromosomes, so that all autosomal genes are available in two copies. For most genes, both copies are expressed without preference. Imprinted genes, however, are expressed depending on their parental origin, being active on the paternal or maternal allele only. To date 73 imprinted genes are known in mouse (www.mgu.har.mrc.ac.uk/research/imprinting), 37 show paternal expression while 36 show maternal expression, indicating no bias for imprinting to occur in one sex or the other. Therefore, two different parental-specific imprinting systems may have evolved in mammals, acting specifically in the paternal or maternal gamete. Similarities and differences between the two imprinting systems will be reviewed, with specific reference to the role of non-coding RNAs and chromatin modifications. The mouse Igf2r/Air cluster is presented as a model of the maternal imprinting system.

Animals↗
PubMed2003

Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response.

The majority of trigeminal ganglia (TGs) are latently infected with alpha-herpesviruses [herpes simplex virus type-1 (HSV-1) and varicella-zoster virus (VZV)]. Whereas HSV-1 periodically reactivates in the TGs, VZV reactivates very rarely. The goal of this study was to determine whether herpesvirus latency is linked to a local immune cell infiltration in human TGs. T cells positive for the CD3 and CD8 markers, and CD68-positive macrophages were found in 30 of 42 examined TGs from 21 healthy individuals. The presence of immune cells correlated constantly with the occurrence of the HSV-1 latency-associated transcript (LAT) and only irregularly with the presence of latent VZV protein. In contrast, uninfected TGs showed no immune cell infiltration. Quantitative RT-PCR revealed that CD8, interferon-gamma, tumor necrosis factor-alpha, IP-10, and RANTES transcripts were significantly induced in TGs latently infected with HSV-1 but not in uninfected TGs. The persisting lymphocytic cell infiltration and the elevated CD8 and cytokine/chemokine expression in the TGs demonstrate for the first time that latent herpesviral infection in humans is accompanied by a chronic inflammatory process at an immunoprivileged site but without any neuronal destruction. The chronic immune response seems to maintain viral latency and influence viral reactivation.

Adolescent↗
PubMed2005

Animal virus replication and RNAi-mediated antiviral silencing in Caenorhabditis elegans.

The worm Caenorhabditis elegans is a model system for studying many aspects of biology, including host responses to bacterial pathogens, but it is not known to support replication of any virus. Plants and insects encode multiple Dicer enzymes that recognize distinct precursors of small RNAs and may act cooperatively. However, it is not known whether the single Dicer of worms and mammals is able to initiate the small RNA-guided RNA interference (RNAi) antiviral immunity as occurs in plants and insects. Here we show complete replication of the Flock house virus (FHV) bipartite, plus-strand RNA genome in C. elegans. We show that FHV replication in C. elegans triggers potent antiviral silencing that requires RDE-1, an Argonaute protein essential for RNAi mediated by small interfering RNAs (siRNAs) but not by microRNAs. This immunity system is capable of rapid virus clearance in the absence of FHV B2 protein, which acts as a broad-spectrum RNAi inhibitor upstream of rde-1 by targeting the siRNA precursor. This work establishes a C. elegans model for genetic studies of animal virus-host interactions and indicates that mammals might use a siRNA pathway as an antiviral response.

Animals↗
PubMed2006

Downregulation of human Cdc6 protein using a lentivirus RNA interference expression vector.

Eukaryotic CDC6 gene function is required for the initiation of DNA replication and is a key regulatory protein during cell cycle progression. The human CDC6 gene is not expressed in most normal tissues, in contrast with its marked expression in proliferating cancer cells. An effective way to explore the gene functions of CDC6 is to knock-down the CDC6 messenger RNA (mRNA) and examine the phenotypic consequences. In this chapter, we describe the construction of a lentivirus vector to express a CDC6 DNA segment. The transcript is able to fold by itself because the sense and antisense regions are complementary. There is a 9-nucleotide (nt) loop region allowing for the short hairpin RNA (shRNA) to form. Cellular ribonucleases process the shRNA into a functional short interfering RNA (siRNA). Down-regulation of Cdc6 protein is confirmed by Western blots.

Cell Cycle Proteins↗