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At least 721 records · Page 40Linked to original sources
PubMed2006

RNA editing of human microRNAs.

BACKGROUND: MicroRNAs (miRNAs) are short RNAs of around 22 nucleotides that regulate gene expression. The primary transcripts of miRNAs contain double-stranded RNA and are therefore potential substrates for adenosine to inosine (A-to-I) RNA editing. RESULTS: We have conducted a survey of RNA editing of miRNAs from ten human tissues by sequence comparison of PCR products derived from matched genomic DNA and total cDNA from the same individual. Six out of 99 (6%) miRNA transcripts from which data were obtained were subject to A-to-I editing in at least one tissue. Four out of seven edited adenosines were in the mature miRNA and were predicted to change the target sites in 3' untranslated regions. For a further six miRNAs, we identified A-to-I editing of transcripts derived from the opposite strand of the genome to the annotated miRNA. These miRNAs may have been annotated to the wrong genomic strand. CONCLUSION: Our results indicate that RNA editing increases the diversity of miRNAs and their targets, and hence may modulate miRNA function.

Adenosine↗
PubMed2004

A pancreatic islet-specific microRNA regulates insulin secretion.

MicroRNAs (miRNAs) constitute a growing class of non-coding RNAs that are thought to regulate gene expression by translational repression. Several miRNAs in animals exhibit tissue-specific or developmental-stage-specific expression, indicating that they could play important roles in many biological processes. To study the role of miRNAs in pancreatic endocrine cells we cloned and identified a novel, evolutionarily conserved and islet-specific miRNA (miR-375). Here we show that overexpression of miR-375 suppressed glucose-induced insulin secretion, and conversely, inhibition of endogenous miR-375 function enhanced insulin secretion. The mechanism by which secretion is modified by miR-375 is independent of changes in glucose metabolism or intracellular Ca2+-signalling but correlated with a direct effect on insulin exocytosis. Myotrophin (Mtpn) was predicted to be and validated as a target of miR-375. Inhibition of Mtpn by small interfering (si)RNA mimicked the effects of miR-375 on glucose-stimulated insulin secretion and exocytosis. Thus, miR-375 is a regulator of insulin secretion and may thereby constitute a novel pharmacological target for the treatment of diabetes.

Animals↗
PubMed2006

miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.

Current understanding of microRNA (miRNA) biology is limited, and antisense oligonucleotide (ASO) inhibition of miRNAs is a powerful technique for their functionalization. To uncover the role of the liver-specific miR-122 in the adult liver, we inhibited it in mice with a 2'-O-methoxyethyl phosphorothioate ASO. miR-122 inhibition in normal mice resulted in reduced plasma cholesterol levels, increased hepatic fatty-acid oxidation, and a decrease in hepatic fatty-acid and cholesterol synthesis rates. Activation of the central metabolic sensor AMPK was also increased. miR-122 inhibition in a diet-induced obesity mouse model resulted in decreased plasma cholesterol levels and a significant improvement in liver steatosis, accompanied by reductions in several lipogenic genes. These results implicate miR-122 as a key regulator of cholesterol and fatty-acid metabolism in the adult liver and suggest that miR-122 may be an attractive therapeutic target for metabolic disease.

AMP-Activated Protein Kinases↗
PubMed2024

ZEB family is a prognostic biomarker and correlates with anoikis and immune infiltration in kidney renal clear cell carcinoma.

BACKGROUND: Zinc finger E-box binding homEeobox 1 (ZEB1) and ZEB2 are two anoikis-related transcription factors. The mRNA expressions of these two genes are significantly increased in kidney renal clear cell carcinoma (KIRC), which are associated with poor survival. Meanwhile, the mechanisms and clinical significance of ZEB1 and ZEB2 upregulation in KIRC remain unknown. METHODS: Through the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, expression profiles, prognostic value and receiver operating characteristic curves (ROCs) of ZEB1 and ZEB2 were evaluated. The correlations of ZEB1 and ZEB2 with anoikis were further assessed in TCGA-KIRC database. Next, miRTarBase, miRDB, and TargetScan were used to predict microRNAs targeting ZEB1 and ZEB2, and TCGA-KIRC database was utilized to discern differences in microRNAs and establish the association between microRNAs and ZEBs. TCGA, TIMER, TISIDB, and TISCH were used to analyze tumor immune infiltration. RESULTS: It was found that ZEB1 and ZEB2 expression were related with histologic grade in KIRC patient. Kaplan-Meier survival analyses showed that KIRC patients with low ZEB1 or ZEB2 levels had a significantly lower survival rate. Meanwhile, ZEB1 and ZEB2 are closely related to anoikis and are regulated by microRNAs. We constructed a risk model using univariate Cox and LASSO regression analyses to identify two microRNAs (hsa-miR-130b-3p and hsa-miR-138-5p). Furthermore, ZEB1 and ZEB2 regulate immune cell invasion in KIRC tumor microenvironments. CONCLUSIONS: Anoikis, cytotoxic immune cell infiltration, and patient survival outcomes were correlated with ZEB1 and ZEB2 mRNA upregulation in KIRC. ZEB1 and ZEB2 are regulated by microRNAs.

Humans↗
PubMed2026

Exploring genomic regions regulating the liver transcriptome and energy homeostasis in pigs.

In pigs, energy homeostasis has an impact on meat quality and health. In a Duroc pig population, 30 quantitative trait locus (QTL) regions associated with fatty acid (FA) composition in adipose tissue, plasma, liver and muscle were previously identified. Mapping of expression quantitative trait locus (eQTL) regions will provide a molecular hypothesis for genotype-phenotype interactions and may allow the identification of shared causal variants, key to increasing our understanding of the genetic regulation of FA composition and energy homeostasis. However, gene expression is impacted by environmental factors, while individual-level allelic imbalance (AI) can be more reliable and can be surveyed via allelic-specific expression (ASE) analysis. Furthermore, treatment of ASE as a quantitative trait allows the identification of allele-specific expression quantitative trait loci (aseQTLs), which are variants whose heterozygosity is linked to the AI of a nearby single-nucleotide polymorphism (SNP), pointing to regulatory elements. In this study, liver was selected as a key metabolic hub with an important role in the regulation of energy homeostasis, and 310 liver RNA sequencing samples were analysed using a combination of (1) eQTL mapping, (2) ASE analysis, and (3) aseQTL mapping methods. A total of 2 188 eQTL regions were identified, mostly cis-eQTL regions (73.17%). ASE analysis reported 1 964 ASE SNPs, associated with 633 genes. Finally, aseQTL mapping reported 64 172 aseQTL, associated with the AI of 31 genes. Colocalisation analysis combined with ASE analysis showed that the expression of FADS1 and FADS2 genes is associated with the polyunsaturated FA composition in several tissues, where microRNA regulation may be present. Finally, in the DGAT2 gene, annotated in a QTL region associated with multiple FAs in adipose tissue, ASE revealed allelic imbalance in the 3' untranslated region (UTR) of this gene. Allelic differential expression can be caused by a 13-bp insertion affecting messenger RNA stability, previously described, exemplifying how allelic imbalance is caused by a post-transcriptional regulatory mechanism undetectable by eQTL mapping. Furthermore, aseQTLs were associated with this gene, linked to a previously identified copy number variant not yet associated with DGAT2 expression. These results demonstrate how ASE analysis and aseQTL mapping can complement eQTL mapping, as they resolved a complex region affected by allelic heterogeneity, a main confounding effect of QTL mapping. In conclusion, the combination of eQTL mapping, ASE analysis and aseQTL mapping allowed the characterisation of the regulation of liver gene expression, improving our understanding of the genetic determinism of energy homeostasis.

Allele-specific expression↗
PubMed2006

Synthetic microRNA designed to target glioma-associated antigen 1 transcription factor inhibits division and induces late apoptosis in pancreatic tumor cells.

PURPOSE: To determine whether the synthetic microRNAs (miRNA) could effectively target tumor cells we designed several miRNA complementary to glioma-associated antigen-1 (Gli-1) mRNA and investigated their ability to inhibit tumor cell proliferation. The sonic hedgehog pathway is an early and late mediator of tumorigenesis in epithelial cancers. Activation of sonic hedgehog signaling seems to precede transformation of tissue stem cells to cancerous stem cells, with the Gli-1 transcription factor functioning as a mediator of environmental signals. Inhibiting cancer cell proliferation by targeting the Gli-1 effector pathway is difficult to achieve by chemotherapeutic agents or short interfering RNA. EXPERIMENTAL DESIGN: We hypothesized that targeting the 3'-untranslated region of Gli-1 mRNA would effectively inhibit tumor cell proliferation. To test this hypothesis, we used synthetic miRNAs of our own design and corresponding duplex/small temporal RNAs by introducing three-nucleotide loops in the 3'-untranslated region Gli-1 sequence of high GU content. RESULTS: We found that miRNA (Gli-1-miRNA-3548) and its corresponding duplex (Duplex-3548) significantly inhibited proliferation of Gli-1+ ovarian (SK-OV-3) and pancreatic (MiaPaCa-2) tumor cells. The miRNAs mediated delayed cell division and activation of late apoptosis in MiaPaCa-2 cells. This is the first demonstration of inhibition of pancreatic tumor cell division by designed miRNA. CONCLUSIONS: Gli-1 miRNAs should significantly add to the general understanding of the mechanisms of metastasis and contribute toward the design of better treatments for epithelial cancers.

3' Untranslated Regions↗
PubMed2006

Vector-based RNAi approaches for stable, inducible and genome-wide screens.

RNA interference (RNAi) has revolutionized the study of biology and offers numerous applications in basic biology as well as in drug discovery research. Since the discovery of RNAi, several tools have been developed to enable loss-of-function studies in mammalian systems. The efficacy of RNAi is dependent on specific and versatile RNAi triggers that have evolved to enable transient, stable and in-vivo applications. Recently developed genome-wide short hairpin RNA (shRNA) and microRNA-adapted short hairpin RNA (shRNAmir) libraries incorporate advances in shRNA design and molecular 'barcodes' to enable more complex RNAi screens and the opportunity to progress to more complex genetics in whole animals.

Animals↗
PubMed2006

Plant fertility defects induced by the enhanced expression of microRNA167.

The plant hormone auxin plays a critical role in regulating plant growth and development. Recent advances have been made in the understanding of auxin response pathways, primarily by the characterization of auxin response mutants in Arabidopsis. In addition, microRNAs (miRNAs) have been shown to be critical regulators of genes important for normal plant development and physiology. However, little is known about possible interactions between miRNAs and hormonal signaling during normal development. Here we show that an Arabidopsis microRNA, miR167, which has a complementary sequence to a portion of the AUXIN RESPONSE FACTOR6 (ARF6) and ARF8 mRNAs, can cause transcript degradation for ARF8, but not for ARF6. We report phenotypic characterizations of 35S::MIR167b transgenic lines, and show that severe 35S::MIR167b transgenic lines had phenotypes similar to those of an arf6 arf8 double mutant. The transgenic phenotypes suggest that miR167 may repress ARF6 at the level of translation. We demonstrate that the transgenic plants are defective in all four whorls of floral organs. In the transgenic flowers, filaments were abnormally short, anthers could not properly release pollen, and pollen grains did not germinate. Our results provide an important link between the miRNA-mediated regulatory pathway of gene expression and the auxin signaling network promoting plant reproductive development.

Arabidopsis↗
PubMed2005

Identification of human fetal liver miRNAs by a novel method.

MicroRNAs (miRNAs) are short 20-25 nucleotides RNA molecules that have been shown to regulate gene expressions in a variety of eukaryotic systems. miRNAs are widespread in eukaryotes and several hundred of miRNAs have been identified, but still a lot of miRNAs have not been detected in various eukaryotic organisms. However, it is not an easy work to clone miRNAs by traditional methods. Here, we describe the identification of 27 miRNAs from a human fetal liver cDNA library by a novel cloning method. Low molecular weight RNA fraction (< or = 200 nt) from fetal liver tissue was extracted, and polyadenylated by poly(A) polymerase. A 5' RNA adaptor was ligated to poly(A)-tailed RNA using T4 RNA ligase. After reverse transcription, the cDNA was amplified by PCR with two adaptor primers. The PCR product with a size about 109 bp was recovered and cloned into T vector. After sequencing, database searching, and expression profiling, 5 novel miRNAs were discovered among other 22 known miRNAs in human fetal liver. These finding indicate that a large diverse population of miRNAs may function to regulate gene expression in hepatocyte.

Cells, Cultured↗
PubMed2002

Two genetic circuits repress the Caenorhabditis elegans heterochronic gene lin-28 after translation initiation.

The heterochronic gene lin-28 of the nematode Caenorhabditis elegans controls the relative timing of diverse developmental events during the animal's larval stages. lin-28 is stage-specifically regulated by two genetic circuits: negatively by the 22-nt RNA lin-4 and positively by the heterochronic gene lin-14. Here, we show that lin-28 is repressed during normal development by a mechanism that acts on its mRNA after translation initiation. We provide evidence that lin-14 inhibits a negative regulation that is independent of the lin-4 RNA and involves the gene daf-12, which encodes a nuclear hormone receptor. The lin-4-independent repression does not affect the initiation of translation on the lin-28 mRNA, and like the lin-4-mediated repression, acts through the gene's 3'-untranslated region. In addition, we find that lin-4 is not sufficient to cause repression of lin-28 if the lin-4-independent circuit is inhibited. Therefore, the lin-4-independent circuit likely contributes substantially to the down-regulation of lin-28 that occurs during normal development. The role of lin-4 may be to initiate or potentiate the lin-4-independent circuit. We speculate that a parallel lin-4-independent regulatory mechanism regulates the expression of lin-14.

Animals↗
PubMed2006

Cell differentiation and organ initiation at the shoot apical meristem.

Plants continuously generate organs at the flanks of their shoot apical meristems (SAMs). The patterns in which these organs are initiated, also called patterns of phyllotaxis, are highly stereotypic and characteristic for a particular species or developmental stage. This stable, predictable behaviour of the meristem has led to the idea that organ initiation must be based on simple and robust mechanisms. This conclusion is less evident, however, if we consider the very dynamic behaviour of the individual cells. How dynamic cellular events are coordinated and how they are linked to the regular patterns of organ initiation is a major issue in plant developmental biology.

Cell Differentiation↗
PubMed2006

Picking pyknons out of the human genome.

In a recent paper in PNAS, Rigoutsos et al. (2006) describe a nonrandom pattern of repeated elements, called pyknons, which are found more frequently in the 3' untranslated regions of genes than in other regions of the human genome. Although it is unclear how pyknons might have arisen, it is possible that they may be involved in a new form of gene regulation.

3' Untranslated Regions↗
PubMed2005

Developmental timing in C. elegans is regulated by kin-20 and tim-1, homologs of core circadian clock genes.

In Caenorhabditis elegans, heterochronic genes constitute a developmental timer that specifies temporal cell fate selection. The heterochronic gene lin-42 is the C. elegans homolog of Drosophila and mammalian period, key regulators of circadian rhythms, which specify changes in behavior and physiology over a 24 hr day/night cycle. We show a role for two other circadian gene homologs, tim-1 and kin-20, in the developmental timer. Along with lin-42, tim-1 and kin-20, the C. elegans homologs of the Drosophila circadian clock genes timeless and doubletime, respectively, are required to maintain late-larval identity and prevent premature expression of adult cell fates. The molecular parallels between circadian and developmental timing pathways suggest the existence of a conserved molecular mechanism that may be used for different types of biological timing.

Animals↗
PubMed2006

A novel function for a ubiquitous plant enzyme pectin methylesterase: the enhancer of RNA silencing.

Co-agroinjection of Nicotiana benthamiana leaves with the pectin methylesterase (proPME) gene and the TMV:GFP vector resulted in a stimulation of virus-induced RNA silencing (inhibition of GFP production, virus RNA degradation, stimulation of siRNAs production). Conversely, co-expression of TMV:GFP with either antisense PME construct or with enzymatically inactive proPME restored synthesis of viral RNA. Furthermore, expression of proPME enhanced the GFP transgene-induced gene silencing accompanied by relocation of the DCL1 protein from nucleus to the cytoplasm and activation of siRNAs and miRNAs production. It was hypothesized that DCL1 relocated to the cytoplasm may use as substrates both miRNA precursor and viral RNA. The capacity for enhancing the RNA silencing is a novel function for the polyfunctional PME.

Carboxylic Ester Hydrolases↗
PubMed2004

AtXRN4 degrades mRNA in Arabidopsis and its substrates include selected miRNA targets.

Messenger RNA degradation is an essential step in gene expression that can be regulated by siRNAs or miRNAs. However, most of our knowledge of in vivo eukaryotic mRNA degradation mechanisms derives from Saccharomyces cerevisiae, which lacks miRNAs and RNAi capability. Using reverse genetic and microarray analyses, we have identified multiple substrates of AtXRN4, the Arabidopsis homolog of the major yeast mRNA degrading exoribonuclease, Xrn1p. Insertional mutation of AtXRN4 leads to accumulation of the 3' end of several mRNAs, in a manner that correlates with increased stability of the 3' end, and is reversed following complementation with AtXRN4. Moreover, 3' products of miRNA-mediated cleavage of SCARECROW-LIKE transcripts and several other miRNA target transcripts are among those that accumulate in xrn4 mutants. The demonstration that an Xrn1p homolog degrades mRNA in a multicellular eukaryote and contributes to the miRNA-mediated decay pathway of selected targets has implications for XRNs in other organisms.

Arabidopsis↗
PubMed2004

Using RNAi to improve plant nutritional value: from mechanism to application.

RNA interference (RNAi) is an ancient mechanism of gene suppression, whose machinery and biological functions are only partially understood. Intensive studies have focused on developing RNAi technologies for treating human diseases and for improving plant traits. Yet application of RNAi to improving the nutritional value of plants for human and animal nutrition, and development of the related RNAi technologies are still in their infancy. Here we discuss current knowledge of plant RNAi function, as well as concepts and strategies for the improvement of plant nutritional value through the development of plant RNAi technologies.

Animals↗
PubMed2003

The small RNA profile during Drosophila melanogaster development.

Small RNAs ranging in size between 20 and 30 nucleotides are involved in different types of regulation of gene expression including mRNA degradation, translational repression, and chromatin modification. Here we describe the small RNA profile of Drosophila melanogaster as a function of development. We have cloned and sequenced over 4000 small RNAs, 560 of which have the characteristics of RNase III cleavage products. A nonredundant set of 62 miRNAs was identified. We also isolated 178 repeat-associated small interfering RNAs (rasiRNAs), which are cognate to transposable elements, satellite and microsatellite DNA, and Suppressor of Stellate repeats, suggesting that small RNAs participate in defining chromatin structure. rasiRNAs are most abundant in testes and early embryos, where regulation of transposon activity is critical and dramatic changes in heterochromatin structure occur.

Animals↗
PubMed2003

Developmental defects by antisense-mediated inactivation of micro-RNAs 2 and 13 in Drosophila and the identification of putative target genes.

Micro-RNAs are a class of small non-coding regulatory RNAs that impair translation by imperfect base pairing to mRNAs. For analysis of their cellular function we injected different miRNA-specific DNA antisense oligonucleotides in Drosophila embryos. In four cases we observed severe interference with normal development, one had a moderate impact and six oligonucleotides did not cause detectable phenotypes. We further used the miR-13a DNA antisense oligonucleotide as a PCR primer on a cDNA library template. In this experimental way we identified nine Drosophila genes, which are characterised by 3' untranslated region motifs that allow imperfect duplex formation with miR-13 or related miRNAs. These genes, which include Sos and Myd88, represent putative targets for miRNA regulation. Mutagenesis of the target motif of two genes followed by transfection in Drosophila Schneider 2 (S2) cells and subsequent reporter gene analysis confirmed the hypothesis that the binding potential of miR-13 is inversely correlated with gene expression.

Animals↗