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PubMed2006

MicroRNAs: fundamental facts and involvement in human diseases.

MicroRNAs (miRNAs) are a group of small noncoding RNAs that have been identified in a variety of organisms. These small, 18-22-nucleotide (nt) RNAs are transcribed as parts of longer molecules called pri-miRNAs, which are processed in the nucleus into hairpin RNAs of 70-100 nt, called pre-miRNAs, by the double-stranded RNA (dsRNA)-specific ribonuclease Drosha. The function of most miRNAs is not known, but for a few members the participation in essential biological processes for the eukaryotic cell is proven. In this review, we summarize how miRNAs were discovered, their biological functions, and importance in animal development, highlighting their function in proliferation, apoptosis, and cell differentiation. Furthermore, we discuss the deregulation of miRNAs in human diseases and their involvement in tumorigenesis.

Gene Expression Regulation, Neoplastic↗

PubMed2006

microRNAs under the microscope.

Once regarded as a biological anomaly, microRNAs (miRNAs) have since been recognized as a prevalent RNA species that regulates a wide array of biological processes, from fat storage and insulin secretion, to apoptosis and cell growth. Recent studies show that miRNAs are expressed at precise times and locations in embryonic development. Moreover, disruption of miRNA processing triggers widespread developmental defects. These findings bolster the idea that miRNAs also regulate multiple aspects of embryonic development. This primer focuses on the emerging roles of miRNAs in development. The basics of miRNA biogenesis and miRNA and mRNA target identification are covered, with an emphasis on miRNA function in development. The primer also features a dialog about current topics in the field.

Animals↗

PubMed2005

Evolution of microRNAs located within Hox gene clusters.

MicroRNAs (miRNAs) form an abundant class of non-coding RNA genes that have an important function in post-transcriptional gene regulation and in particular modulate the expression of developmentally important transcription factors including Hox genes. Two families of microRNAs are genomically located in intergenic regions in the Hox clusters of vertebrates. Here we describe their evolution in detail. We show that the micro RNAs closely follow the patterns of protein evolution in the Hox clusters, which is characterized by cluster duplications followed by differential gene loss.

Animals↗

PubMed2005

Specific effects of microRNAs on the plant transcriptome.

Most plant microRNAs (miRNAs) have perfect or near-perfect complementarity with their targets. This is consistent with their primary mode of action being cleavage of target mRNAs, similar to that induced by perfectly complementary small interfering RNAs (siRNAs). However, there are natural targets with up to five mismatches. Furthermore, artificial siRNAs can have substantial effects on so-called off-targets, to which they have only limited complementarity. By analyzing the transcriptome of plants overexpressing different miRNAs, we have deduced a set of empirical parameters for target recognition. Compared to artificial siRNAs, authentic plant miRNAs appear to have much higher specificity, which may reflect their coevolution with the remainder of the transcriptome. We also demonstrate that miR172, previously thought to act primarily by translational repression, can efficiently guide mRNA cleavage, although the effects on steady-state levels of target transcripts are obscured by strong feedback regulation. This finding unifies the view of plant miRNA action.

Base Pairing↗

PubMed2006

RNA polymerase III transcribes human microRNAs.

Prior work demonstrates that mammalian microRNA (miRNA or miR) expression requires RNA polymerase II (Pol II). However, the transcriptional requirements of many miRNAs remain untested. Our genomic analysis of miRNAs in the human chromosome 19 miRNA cluster (C19MC) revealed that they are interspersed among Alu repeats. Because Alu transcription occurs through RNA Pol III recruitment, and we found that Alu elements upstream of C19MC miRNAs retain sequences important for Pol III activity, we tested the promoter requirements of C19MC miRNAs. Chromatin immunoprecipitation and cell-free transcription assays showed that Pol III, but not Pol II, is associated with miRNA genomic sequence and sufficient for transcription. Moreover, the mature miRNA sequences of approximately 50 additional human miRNAs lie within Alu and other known repetitive elements. These findings extend the current view of miRNA origins and the transcriptional machinery driving their expression.

Alu Elements↗

PubMed2004

Mouse microRNA-23b regulates expression of Hes1 gene in P19 cells.

MicroRNAs (miRNAs) are abundant class of approximately 21-25 nts small endogenous RNAs. Recently several hundred miRNAs have been identified from diverse species; nematodes, insects, plants, and animals. These small RNAs can regulate gene expression at a post-transcriptional level by interacting with their target mRNAs. Interaction of these RNAs causes either repression of translation or RNAi-dependent cleavage of target RNAs. It has been recently found that they have critical regulatory roles in embryogenesis, development, differentiation, cellular proliferation, apoptosis, and so on. However, identifications of the target of the target of miRNAs have been almost unknown, especially in vertebrates. Here we show that Hairy/enhancer of split protein (Hes1), a bHLH transcriptional repressor functioning in neuronal differentiation, is a target of mouse miRNA-23b (miR-23b).

Animals↗

PubMed2006

Transgene-like animal models using intronic microRNAs.

Transgenic animal models are valuable tools for testing gene functions and drug mechanisms in vivo. They are also the best similitude of a human body for etiological and pathological research of diseases. All pharmaceutically developed drugs must be proven safe and effective in animals before approval by the Food and Drug Administration to be used in clinical trials. To this end, the transgenic animal models of human diseases serve as a front line for drug evaluation. However, there is currently no transgenic animal model for microRNA (miRNA) research. miRNAs, small single-stranded regulatory RNAs capable of silencing intracellular gene transcripts that contain either complete or partial complementarity to the miRNAs, are useful for the design and development of new therapies against cancer polymorphism and viral mutation. Recently, varieties of natural miRNAs have been found to be derived from hairpin-like RNA precursors in almost all eukaryotes, including yeast (Schizosaccharomyces pombe), plant (Arabidopsis), nematode (Caenorhabditis elegans), fly (Drosophila melanogaster), fish, mouse, and human, involving intracellular defense against viral infections and regulation of certain gene expressions during development. To facilitate the miRNA research in vivo, we have developed a state-of-the-art transgenic strategy for silencing specific genes in zebrafish, chicken, and mouse, using intronic miRNAs. By insertion of a hairpin-like pre-miRNA structure into the intron region of a gene, we have found that mature miRNAs were successfully transcribed by RNA polymerase (Pol)-II, coexpressed with the encoding gene transcript, and excised out of the encoding gene transcript by natural RNA splicing and processing mechanisms. In conjunction with retroviral transfection systems, the hairpin-like pre-miRNA construct was further inserted into the intron of a cellular gene for tissue-specific expression regulated by the gene promoter. Because the retroviral vectors were randomly integrated into the genome of its host cell, the most effective transgenic animal can be selected and propagated to be a stable transgenic line for future research. Here, we have shown for the first time that transgene-like animal models were generated using the intronic miRNA-expressing system described previously, which has been proven to be useful for both miRNA research and in vivo evaluation of miRNA-associated target genes.

Animals↗

PubMed2006

Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model.

BACKGROUND: microRNAs (miRNAs) are a group of non-coding single stranded RNAs measuring approximately 22 nt in length that have been found to control cell growth, differentiation and apoptosis. miRNAs negatively regulate their target genes and recently have been implicated in tumourigenesis. Furthermore, miRNA expression profiling correlates with various cancers, with these genes thought to act as both tumour suppressors and oncogenes. ret/PTC 1 is an oncogene with constitutive kinase activity implicated in the development of papillary thyroid carcinoma (PTC). This rearrangement leads to aberrant MAPK activation that is implicated in PTC tumourigenesis. AIM: The aim of this study was to identify the effect that ret/PTC 1 has on transcription and post-transcriptional regulation in PTC by using DNA microarray and microRNA analysis. RESULTS: DNA microarray analysis revealed a group of genes differentially expressed between normal thyroid cell lines and those harbouring a ret/PTC 1 rearrangement.Furthermore, a unique miRNA expression signature differentiated between PTC cell lines with ret/PTC 1 and a normal thyroid cell line. 21 miRNAs showed significant overexpression and 14 miRNAs showed underexpression in these cell lines when compared to normal thyroid. Several of these up/down regulated miRNAs may be involved in PTC pathogenesis.

Biomarkers, Tumor↗

PubMed2026

A muskrat tissue atlas of small non-coding RNAs and their regulatory roles in muskrat musk secretion.

Muskrat musk, secreted by the male muskrat scent gland during the secretion period, is a valuable natural product with promising pharmacological activities. Its synthesis is regulated not only by coding genes but also by small non-coding RNAs (sncRNAs). However, a comprehensive tissue atlas of sncRNAs in muskrats has been lacking. To address this issue, we systematically profiled the expression levels of 6 sncRNA categories (piRNA [PIWI-interacting RNA], miRNA [microRNA], snoRNA [small nucleolar RNA], snRNA [small nuclear RNA], tRNA [transfer RNA], and other RNAs) across 13 tissues of the muskrat via deep sequencing. We identified 23,957 sncRNAs (∼ 65%) exhibiting tissue-specific expression patterns throughout the body. The results show that miRNA is the main contributor to tissue specificity. Eleven tissues showed a significantly higher number of miRNA-5p arm expressions compared to the 3p arm, although the brain was an exception. Quantitative results imply that miR-477-3p/5p and miR-794-3p are potentially involved in the regulation of muskrat musk synthesis and secretion in the muskrat scent glands. Their target genes were enriched in pathways related to energy supply, lipid metabolism, and cyclic morphological changes of the scent gland. Furthermore, we constructed a set of co-expressed miRNAs based on the hormone-dominated "brain-testis-scent gland" axis and the energy metabolism-dominated "brain-liver-scent gland" axis. These results provide the most comprehensive description to date of tissue-specific and ubiquitous sncRNAs in individual muskrat tissues. We anticipate that these data will enhance the understanding of the molecular regulation underlying muskrat musk synthesis and secretion.

Animals↗

PubMed2006

Design of expression vectors for RNA interference based on miRNAs and RNA splicing.

RNA interference (RNAi) mediates sequence-specific post-transcriptional gene silencing in many eukaryotes and is used for reverse genetic studies and therapeutics. RNAi is triggered by double-stranded small interfering RNAs (siRNAs), which can be processed from small hairpin RNAs generated from an expression vector. In some recently described vectors, the siRNAs are expressed from synthetic stem-loop precursors of microRNAs (miRNAs) driven by polymerase II promoters. We have designed new RNAi vectors, designated pSM155 and pSM30, that take into consideration miRNA processing and RNA splicing by placing the miRNA-based artificial miRNA expression cassettes inside of synthetic introns. Like the original miRNA vectors, we show that the pSM155 and pSM30 constructs efficiently down-regulate expression of firefly luciferase and an endogenous gene, phospholipase D2. Moreover, the expression of a coexpressed fluorescent marker is substantially improved by this new design. Another improvement of these new vectors is incorporation of two inverted BsmBI sites placed internal to the arms of the new miRNA-based vectors, so oligos used for cloning are shorter and the cost is reduced. These RNAi vectors thus provide new tools for gene suppression.

Base Sequence↗

PubMed2005

Mapping and expression studies of the mir17-92 cluster on pig chromosome 11.

We have identified the first porcine microRNA (miRNA) cluster (the mir17-92 cluster) and localized it to the q-arm of pig Chromosome 11. The miRNA cluster was found by sequence similarity search with human miRNA sequences against the pig genomic data generated within the Sino-Danish pig genome project. The resulting data contained three complete and two incomplete miRNA precursors of seven miRNAs from the human mir17-92 cluster. Because there is a 100% sequence identity between the four pig miRNAs and the corresponding human miRNAs, the sequences of three unavailable pig miRNAs were derived from the human data. The expression profiles of seven studied miRNAs were analyzed by hybridization to Northern blots containing five porcine tissues: cerebellum, cortex, hippocampus, kidney, and liver. In order to determine the localization of the mir17-92 cluster in the pig genome, we mapped it by PCR in the porcine somatic cell hybrid (SCH) panel and in the INRA-University of Minnesota (INRA-UMN) porcine radiation hybrid (IMpRH) panel. The PCR results enabled us to localize this cluster to the q-arm of pig Chromosome 11 and map it in relation to two microsatellites. Our study presents the first expression analyses of miRNAs in pig and adds information for further functional studies in this species.

Animals↗

PubMed2006

Computational identification of microRNAs and their targets.

MicroRNAs (miRNAs) are one class of newly identified riboregulators of gene expression in many eukaryotic organisms. They play important roles in multiple biological and metabolic processes, including developmental timing, signal transduction, cell maintenance and differentiation, diseases and cancers. miRNAs regulate gene expression at the posttranscriptional level by directly cleaving targeted mRNAs or repressing translation. Although the founding members of miRNAs were discovered by genetic screening approaches, experimental approaches were limited by their low efficiency, time consuming, and high cost. As an alternative, computational approaches were developed. Computational approaches for identifying miRNAs are based on the following major characteristics of miRNAs: hairpin-shaped secondary structures, high conservation for some miRNAs, and high minimal folding free energy index (MFEI). Computational approaches also play an important role in identifying miRNA targets. A majority of known miRNAs and their targets were identified by computational approaches. Several web-based or non-web-based computer software programs are publicly available for predicting miRNAs and their targets.

Animals↗

PubMed2006

Overgrowth caused by misexpression of a microRNA with dispensable wild-type function.

MicroRNAs (miRNAs) represent an abundant class of non-coding RNAs that negatively regulate gene expression, primarily at the post-transcriptional level. miRNA genes are frequently located in proximity to fragile chromosomal sites associated with cancers and amplification of a miRNA cluster has been correlated with the etiology of lymphomas and solid tumors. The oncogenic potential of a miRNA polycistron has recently been demonstrated in vivo. Here, we show that misexpression of the Drosophila miRNA mirvana/mir-278 in the developing eye causes massive overgrowth, in part due to inhibition of apoptosis. A single base substitution affecting the mature miRNA blocks the gain-of-function phenotype but is not associated with a detectable reduction-of-function phenotype when homozygous. This result demonstrates that misexpressed miRNAs may acquire novel functions that cause unscheduled proliferation in vivo and thus exemplifies the potential of miRNAs to promote tumor formation.

Animals↗

PubMed2006

The role of microRNAs in normal hematopoiesis and hematopoietic malignancies.

Over the past few years, it has become evident that microRNAs (miRNAs) play an important regulatory role in various biological processes. Much effort has been put into the elucidation of their biogenesis, and this has led to the general concept that a number of key regulators are shared with the processing machinery of small interfering RNAs. Despite the recognition that several miRNAs play crucial roles in normal development and in diseases, little is known about their exact molecular function and the identity of their target genes. In this review, we report on the biological relevance of miRNAs for the differentiation of normal hematopoietic cells and on the contribution of deregulated miRNA expression in their malignant counterparts.

Animals↗

PubMed2006

MicroRNA-cancer connection: the beginning of a new tale.

Cancer initiation and progression can involve microRNAs (miRNA), which are small noncoding RNAs that can regulate gene expression. Their expression profiles can be used for the classification, diagnosis, and prognosis of human malignancies. Loss or amplification of miRNA genes has been reported in a variety of cancers, and altered patterns of miRNA expression may affect cell cycle and survival programs. Germ-line and somatic mutations in miRNAs or polymorphisms in the mRNAs targeted by miRNAs may also contribute to cancer predisposition and progression. We propose that alterations in miRNA genes play a critical role in the pathophysiology of many, perhaps all, human cancers.

Animals↗

PubMed2006

Lower expression of genes near microRNA in C. elegans germline.

BACKGROUND: MicroRNAs (miRNAs) are recently discovered short non-protein-coding RNA molecules. miRNAs are increasingly implicated in tissue-specific transcriptional control and particularly in development. Because there is mounting evidence for the localized component of transcriptional control, we investigated if there is a distance-dependent effect of miRNA. RESULTS: We analyzed gene expression levels around the 84 of 113 know miRNAs for which there are nearby gene that were measured in the data in two independent C. elegans expression data sets. The expression levels are lower for genes in the vicinity of 59 of 84 (71%) miRNAs as compared to genes far from such miRNAs. Analysis of the genes with lower expression in proximity to the miRNAs reveals increased frequency matching of the 7 nucleotide "seed"s of these miRNAs. CONCLUSION: We found decreased messenger RNA (mRNA) abundance, localized within a 10 kb of chromosomal distance of some miRNAs, in C. elegans germline. The increased frequency of seed matching near miRNA can explain, in part, the localized effects.

Animals↗

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↗

PubMed2005

A novel C. elegans zinc finger transcription factor, lsy-2, required for the cell type-specific expression of the lsy-6 microRNA.

The two Caenorhabditis elegans gustatory neurons, ASE left (ASEL) and ASE right (ASER) are morphologically bilaterally symmetric, yet left/right asymmetric in function and in the expression of specific chemosensory signaling molecules. The ASEL versus ASER cell-fate decision is controlled by a complex gene regulatory network composed of microRNAs (miRNAs) and transcription factors. Alterations in the activities of each of these regulatory factors cause a complete lateral cell-fate switch. Here, we describe lsy-2, a novel C2H2 zinc finger transcription factor that is required for the execution of the ASEL stable state. In lsy-2 null mutants, the ASEL neuron adopts the complete ASER gene expression profile, including both upstream regulatory and terminal effector genes. The normally left/right asymmetric ASE neurons are therefore ;symmetrized' in lsy-2 mutants. Cell-specific rescue experiments indicate that lsy-2 is required autonomously in ASEL for the activation of ASEL-specifying factors and the repression of ASER-specifying factors. Genetic epistasis experiments demonstrate that lsy-2 exerts its activity by regulating the transcription of the lsy-6 miRNA in the ASEL neuron, thereby making lsy-2 one of the few factors known to control the cell-type specificity of miRNA gene expression.

Amino Acid Sequence↗