MicroRNAs (miRNAs) are short, non-coding RNA regulators of protein coding genes. miRNAs play a very important role in diverse biological processes and various diseases. Many algorithms are able to predict miRNA genes and their targets, but their transcription regulation is still under investigation. It is generally believed that intragenic miRNAs (located in introns or exons of protein coding genes) are co-transcribed with their host genes and most intergenic miRNAs transcribed from their own RNA polymerase II (Pol II) promoter. However, the length of the primary transcripts and promoter organization is currently unknown.
We performed Pol II chromatin immunoprecipitation (ChIP)-chip using a custom array surrounding regions of known miRNA genes. To identify the true core transcription start sites of the miRNA genes we developed a new tool (CPPP). We showed that miRNA genes can be transcribed from promoters located several kilobases away and that their promoters share the same general features as those of protein coding genes. Finally, we found evidence that as many as 26% of the intragenic miRNAs may be transcribed from their own unique promoters.
miRNA promoters have similar features to those of protein coding genes, but miRNA transcript organization is more complex.
microRNAs (miRNAs) are tiny endogenous RNAs that have been discovered in animals and plants, and direct the post-transcriptional regulation of target mRNAs for degradation or translational repression via binding to the 3'UTRs and the coding exons. To gain insight into the biological role of miRNAs, it is essential to identify the full repertoire of mRNA targets (target genes). A number of computer programs have been developed for miRNA-target prediction. These programs essentially focus on potential binding sites in 3'UTRs, which are recognized by miRNAs according to specific base-pairing rules.
Here, we introduce a novel method for miRNA-target prediction that is entirely independent of existing approaches. The method is based on the hypothesis that transcription of a miRNA and its target genes tend to be co-regulated by common transcription factors. This hypothesis predicts the frequent occurrence of common cis-elements between promoters of a miRNA and its target genes. That is, our proposed method first identifies putative cis-elements in a promoter of a given miRNA, and then identifies genes that contain common putative cis-elements in their promoters. In this paper, we show that a significant number of common cis-elements occur in ~28% of experimentally supported human miRNA-target data. Moreover, we show that the prediction of human miRNA-targets based on our method is statistically significant. Further, we discuss the random incidence of common cis-elements, their consensus sequences, and the advantages and disadvantages of our method.
This is the first report indicating prevalence of transcriptional regulation of a miRNA and its target genes by common transcription factors and the predictive ability of miRNA-targets based on this property.
MicroRNAs (miRNAs) are noncoding RNAs with important roles in regulating gene expression. In studying the earliest nuclear steps of miRNA biogenesis, we observe that primary miRNA (pri-miRNA) transcripts retained at transcription sites due to the deletion of 3′-end processing signals are converted more efficiently into precursor miRNAs (pre-miRNAs) than pri-miRNAs that are cleaved, polyadenylated, and released. Flanking exons, which also increase retention at transcription sites, likewise contribute to increased levels of intronic pri-miRNAs. Consistently, efficiently processed endogenous pri-miRNAs are enriched in chromatin-associated nuclear fractions. In contrast, pri-miRNAs that accumulate to high nuclear levels after cleavage and polyadenylation because of the presence of a viral RNA element (the ENE of the Kaposi's sarcoma–associated herpes virus polyadenylated nuclear RNA) are not efficiently processed to precursor or mature miRNAs. Exogenous pri-miRNAs unexpectedly localize to nuclear foci containing splicing factor SC35; yet these foci are unlikely to represent sites of miRNA transcription or processing. Together, our results suggest that pri-miRNA processing is enhanced by coupling to transcription.
MicroRNAs (miRNAs) are small 22-25 nucleotides long non-coding RNAs, that are conserved during evolution, and control gene expression in metazoan animals, plants, viruses, and bacteria primarily at post-transcriptional and transcriptional levels. MiRNAs ultimately regulate target gene expression by degrading the corresponding mRNA and/or inhibiting their translation. Currently, the critical functions of miRNAs have been established in regulating immune system, cell proliferation, differentiation and development, cancer and cell cycle by as yet unknown control mechanism. MiRNAs play an essential role in malignancy, and as tumour suppressors and oncogenes. Thus, discovery of new miRNAs will probably change the landscape of cancer genetics. Significantly different miRNA profiles can be assigned to various types of tumours, which could serve as phenotypic signatures for different cancers for their exploitation in cancer diagnostics, prognostics and therapeutics. If miRNA profiles can accurately predict malignancies, this technology could be exploited as a tool to surmount the diagnostic challenges. This review provides comprehensive and systematic information on miRNA biogenesis and their implications in human health.
Biogenesis; cancer-gene expression; MicroRNA; oncogene
MicroRNAs (miRNAs) are a novel class of non-coding small RNAs. In mammalian cells, miRNAs repress the translation of messenger RNAs (mRNAs) or degrade mRNAs. miRNAs play important roles in development and differentiation, and they are also implicated in aging, and oncogenesis. Predictions of targets of miRNAs suggest that they may regulate more than one-third of all genes. The overall functions of mammalian miRNAs remain unclear. Combinatorial regulation by transcription factors alone or miRNAs alone offers a wide range of regulatory programs. However, joining transcriptional and post-transcriptional regulatory mechanisms enables higher complexity regulatory programs that in turn could give cells evolutionary advantages. Investigating coordinated regulation of genes by miRNAs and transcription factors (TFs) from a statistical standpoint is a first step that may elucidate some of their roles in various biological processes.
Here, we studied the nature and scope of coordination among regulators from the transcriptional and miRNA regulatory layers in the human genome. Our findings are based on genome wide statistical assessment of regulatory associations ("interactions") among the sets of predicted targets of miRNAs and sets of putative targets of transcription factors. We found that combinatorial regulation by transcription factor pairs and miRNA pairs is much more abundant than the combinatorial regulation by TF-miRNA pairs. In addition, many of the strongly interacting TF-miRNA pairs involve a subset of master TF regulators that co-regulate genes in coordination with almost any miRNA. Application of standard measures for evaluating the degree of interaction between pairs of regulators show that strongly interacting TF-miRNA, TF-TF or miRNA-miRNA pairs tend to include TFs or miRNAs that regulate very large numbers of genes. To correct for this potential bias we introduced an additional Bayesian measure that incorporates not only how significant an interaction is but also how strong it is. Putative pairs of regulators selected by this procedure are more likely to have biological coordination. Importantly, we found that the probability of a TF-miRNA pair forming feed forward loops with its common target genes (where the miRNA simultaneously suppresses the TF and many of its targets) is increased for strongly interacting TF-miRNA pairs.
Genes are more likely to be co-regulated by pairs of TFs or pairs of miRNAs than by pairs of TF-miRNA, perhaps due to higher probability of evolutionary duplication events of shorter DNA sequences. Nevertheless, many gene sets are reciprocally regulated by strongly interacting pairs of TF-miRNA, which suggests an effective mechanism to suppress functionally related proteins. Moreover, the particular type of feed forward loop (with two opposing modes where the TF activates its target genes or the miRNA simultaneously suppresses this TF and the TF-miRNA joint target genes) is more prevalent among strongly interacting TF-miRNA pairs. This may be attributed to a process that prevents waste of cellular resources or a mechanism to accelerate mRNA degradation.
MicroRNAs (miRNA) are ∼21 nucleotide-long non-coding small RNAs, which function as post-transcriptional regulators in eukaryotes. miRNAs play essential roles in regulating plant growth and development. In recent years, research into the mechanism and consequences of miRNA action has made great progress. With whole genome sequence available in such plants as Arabidopsis thaliana, Oryza sativa, Populus trichocarpa, Glycine max, etc., it is desirable to develop a plant miRNA database through the integration of large amounts of information about publicly deposited miRNA data. The plant miRNA database (PMRD) integrates available plant miRNA data deposited in public databases, gleaned from the recent literature, and data generated in-house. This database contains sequence information, secondary structure, target genes, expression profiles and a genome browser. In total, there are 8433 miRNAs collected from 121 plant species in PMRD, including model plants and major crops such as Arabidopsis, rice, wheat, soybean, maize, sorghum, barley, etc. For Arabidopsis, rice, poplar, soybean, cotton, medicago and maize, we included the possible target genes for each miRNA with a predicted interaction site in the database. Furthermore, we provided miRNA expression profiles in the PMRD, including our local rice oxidative stress related microarray data (LC Sciences miRPlants_10.1) and the recently published microarray data for poplar, Arabidopsis, tomato, maize and rice. The PMRD database was constructed by open source technology utilizing a user-friendly web interface, and multiple search tools. The PMRD is freely available at http://bioinformatics.cau.edu.cn/PMRD. We expect PMRD to be a useful tool for scientists in the miRNA field in order to study the function of miRNAs and their target genes, especially in model plants and major crops.
microRNAs (miRNAs) are short, 21–24 nucleotide (nt), non-coding RNAs that post-transcriptionally regulate the expression of messenger RNAs (mRNAs). Through the regulation of their cognate mRNAs, miRNAs control diverse aspects of biology, including development, cellular differentiation, proliferation, metabolism and death. Thus, miRNAs play a critical role in the determination of normal cellular physiology and misexpression of miRNAs leads to pathological responses. Understanding the mechanisms that control miRNA expression is an important step forward as novel functions of miRNAs continue to be uncovered. In addition to transcriptional regulation, multiple pathways of post-transcriptional modulation of miRNA expression have been uncovered. In this review we discuss the role of the Smads in the regulation of miRNA processing in response to Transforming growth factor β (TGFβ) stimulation.
microRNA; miRNA; TGFβ; BMP; smads; biogenesis; drosha; processing
microRNAs (miRNAs) are small, endogenous RNAs of 20∼25 nucleotides, processed from stem-loop regions of longer RNA precursors. Plant miRNAs act as negative regulators of target mRNAs predominately by slicing target transcripts, and a number of miRNAs play important roles in development. We analyzed a number of published datasets from Arabidopsis thaliana to characterize novel miRNAs, novel miRNA targets, and miRNA-regulated developmental changes in gene expression. These data include microarray profiling data and small RNA (sRNA) deep sequencing data derived from miRNA biogenesis/transport mutants, microarray profiling data of mRNAs in a developmental series, and computational predictions of conserved genomic stem-loop structures. Our conservative analyses identified five novel mature miRNAs and seven miRNA targets, including one novel target gene. Two complementary miRNAs that target distinct mRNAs were encoded by one gene. We found that genes targeted by known miRNAs, and genes up-regulated or down-regulated in miRNA mutant inflorescences, are highly expressed in the wild type inflorescence. In addition, transcripts upregulated within the mutant inflorescences were abundant in wild type leaves and shoot meristems and low in pollen and seed. Downregulated transcripts were abundant in wild type pollen and seed and low in shoot meristems, roots and leaves. Thus, disrupting miRNA function causes the inflorescence transcriptome to resemble the leaf and meristem and to differ from pollen and seed. Applications of our computational approach to other species and the use of more liberal criteria than reported here will further expand the number of identified miRNAs and miRNA targets. Our findings suggest that miRNAs have a global role in promoting vegetative to reproductive transitions in A. thaliana.
There is growing interest in the epigenetic mechanisms that impact human health and disease, including the role of microRNAs (miRNAs). These small (18–25 nucleotide), evolutionarily conserved, non-coding RNA molecules regulate gene expression in a post-transcriptional manner. Several well-orchestered regulatory mechanisms involving miRNAs have been identified, with the potential to target multiple signaling pathways dysregulated in cancer. Since the initial discovery of miRNAs, there has been progress towards therapeutic applications, and several natural and synthetic chemopreventive agents also have been evaluated as modulators of miRNA expression in different cancer types. This review summarizes the most up-to-date information related to miRNA biogenesis, and critically evaluates proposed miRNA regulatory mechanisms in relation to cancer signaling pathways, as well as other epigenetic modifications (DNA methylation patterns, histone marks) and their involvement in drug resistance. We also discuss the mechanisms by which dietary factors regulate miRNA expression, in the context of chemoprevention versus therapy.
MicroRNAs (miRNAs) exist pervasively across viruses, plants and animals and play important roles in the post-transcriptional regulation of genes. In the common carp, miRNA targets have not been investigated. In model species, single-nucleotide polymorphisms (SNPs) have been reported to impair or enhance miRNA regulation as well as to alter miRNA biogenesis. SNPs are often associated with diseases or traits. To date, no studies into the effects of SNPs on miRNA biogenesis and regulation in the common carp have been reported.
Using homology-based prediction combined with small RNA sequencing, we have identified 113 common carp mature miRNAs, including 92 conserved miRNAs and 21 common carp specific miRNAs. The conserved miRNAs had significantly higher expression levels than the specific miRNAs. The miRNAs were clustered into three phylogenetic groups. Totally 394 potential miRNA binding sites in 206 target mRNAs were predicted for 83 miRNAs. We identified 13 SNPs in the miRNA precursors. Among them, nine SNPs had the potential to either increase or decrease the energy of the predicted secondary structures of the precursors. Further, two SNPs in the 3’ untranslated regions of target genes were predicted to either disturb or create miRNA-target interactions.
The common carp miRNAs and their target genes reported here will help further our understanding of the role of miRNAs in gene regulation. The analysis of the miRNA-related SNPs and their effects provided insights into the effects of SNPs on miRNA biogenesis and function. The resource data generated in this study will help advance the study of miRNA function and phenotype-associated miRNA identification.
miRNAs; Targets; SNPs; miRNA biogenesis; Common carp
MicroRNAs (miRNAs) are small, non-coding RNAs that play critical roles in post-transcriptional gene regulation. In plants, mature miRNAs pair with complementary sites on mRNAs and subsequently lead to cleavage and degradation of the mRNAs. Many miRNAs target mRNAs that encode transcription factors; therefore, they regulate the expression of many downstream genes. In this study, we carry out a survey of Arabidopsis microRNA genes in response to UV-B radiation, an important adverse abiotic stress. We develop a novel computational approach to identify microRNA genes induced by UV-B radiation and characterize their functions in regulating gene expression. We report that in A. thaliana, 21 microRNA genes in 11 microRNA families are upregulated under UV-B stress condition. We also discuss putative transcriptional downregulation pathways triggered by the induction of these microRNA genes. Moreover, our approach can be directly applied to miRNAs responding to other abiotic and biotic stresses and extended to miRNAs in other plants and metazoans.
integration of heterogeneous data; microRNA gene; UV-B responsive
MicroRNAs (miRNAs) are short non-coding RNA molecules that act as post-transcriptional regulators and affect the regulation of protein-coding genes. Mostly transcribed by PolII, miRNA genes are regulated at the transcriptional level similarly to protein-coding genes. In this study we focus on human miRNAs. These miRNAs are involved in a variety of pathways and can affect many diseases. Our interest is on possible deregulation of the transcription initiation of the miRNA encoding genes, which is facilitated by variations in the genomic sequence of transcriptional control regions (promoters).
Our aim is to provide an online resource to facilitate the investigation of the potential effects of single nucleotide polymorphisms (SNPs) on miRNA gene regulation. We analyzed SNPs overlapped with predicted transcription factor binding sites (TFBSs) in promoters of miRNA genes. We also accounted for the creation of novel TFBSs due to polymorphisms not present in the reference genome. The resulting changes in the original TFBSs and potential creation of new TFBSs were incorporated into the Dragon Database of Polymorphic Regulation of miRNA genes (dPORE-miRNA).
The dPORE-miRNA database enables researchers to explore potential effects of SNPs on the regulation of miRNAs. dPORE-miRNA can be interrogated with regards to: a/miRNAs (their targets, or involvement in diseases, or biological pathways), b/SNPs, or c/transcription factors. dPORE-miRNA can be accessed at http://cbrc.kaust.edu.sa/dpore and http://apps.sanbi.ac.za/dpore/. Its use is free for academic and non-profit users.
MicroRNAs (miRNAs) are short non-coding RNA molecules participating in post-transcriptional regulation of gene expression. There have been many efforts to discover miRNA precursors (pre-miRNAs) over the years. Recently, ab initio approaches obtain more attention because that they can discover species-specific pre-miRNAs. Most ab initio approaches proposed novel features to characterize RNA molecules. However, there were fewer discussions on the associated classification mechanism in a miRNA predictor.
This study focuses on the classification algorithm for miRNA prediction. We develop a novel ab initio method, miR-KDE, in which most of the features are collected from previous works. The classification mechanism in miR-KDE is the relaxed variable kernel density estimator (RVKDE) that we have recently proposed. When compared to the famous support vector machine (SVM), RVKDE exploits more local information of the training dataset. MiR-KDE is evaluated using a training set consisted of only human pre-miRNAs to predict a benchmark collected from 40 species. The experimental results show that miR-KDE delivers favorable performance in predicting human pre-miRNAs and has advantages for pre-miRNAs from the genera taxonomically distant to humans.
We use a novel classifier of which the characteristic of exploiting local information is particularly suitable to predict species-specific pre-miRNAs. This study also provides a comprehensive analysis from the view of classification mechanism. The good performance of miR-KDE encourages more efforts on the classification methodology as well as the feature extraction in miRNA prediction.
MicroRNAs (miRNAs) are recently discovered small non-coding RNAs that play pivotal roles in gene expression, specifically at the post-transcriptional level in plants and animals. Identification of miRNAs in large number of diverse plant species is important to understand the evolution of miRNAs and miRNA-targeted gene regulations. Now-a-days, publicly available databases play a central role in the in-silico biology. Because, at least ~21 miRNA families are conserved in higher plants, a homology based search using these databases can help identify orthologs or paralogs in plants.
We searched all publicly available nucleotide databases of genome survey sequences (GSS), high-throughput genomics sequences (HTGS), expressed sequenced tags (ESTs) and nonredundant (NR) nucleotides and identified 682 miRNAs in 155 diverse plant species. We found more than 15 conserved miRNA families in 11 plant species, 10 to14 families in 10 plant species and 5 to 9 families in 29 plant species. Nineteen conserved miRNA families were identified in important model legumes such as Medicago, Lotus and soybean. Five miRNA families – miR319, miR156/157, miR169, miR165/166 and miR394 – were found in 51, 45, 41, 40 and 40 diverse plant species, respectively. miR403 homologs were found in 16 dicots, whereas miR437 and miR444 homologs, as well as the miR396d/e variant of the miR396 family, were found only in monocots, thus providing large-scale authenticity for the dicot- and monocot-specific miRNAs. Furthermore, we provide computational and/or experimental evidence for the conservation of 6 newly found Arabidopsis miRNA homologs (miR158, miR391, miR824, miR825, miR827 and miR840) and 2 small RNAs (small-85 and small-87) in Brassica spp.
Using all publicly available nucleotide databases, 682 miRNAs were identified in 155 diverse plant species. By combining the expression analysis with the computational approach, we found that 6 miRNAs and 2 small RNAs that have been identified only in Arabidopsis thus far, are also conserved in Brassica spp. These findings will be useful for tracing the evolution of small RNAs by examining their expression in common ancestors of the Arabidopsis-Brassica lineage.
MicroRNAs (miRNAs) are a class of small non-coding RNAs which function in gene regulation with an important role in cell proliferation, maturation, and activity. The regulatory role of these small RNA molecules has recently begun to be explored in ovarian cells, uncovering their influence on gonadal development, steroidogenesis, apoptosis, ovulation, and corpus luteum development. This emerging area of research has extended and reshaped our understanding on how ovarian function is regulated. Here, we review the current understanding of miRNA biogenesis, the role and mechanism that miRNAs play in post-transcriptional gene expression regulation, and specifically the current evidence of miRNA involvement in ovarian development and function. Future comprehensive understanding of the role of miRNAs in the ovary in both physiological and pathological conditions may offer new treatment strategies for infertility and other ovarian disorders.
microRNA; gene regulation; ovaries; small RNA
MicroRNAs (miRNAs) are endogenously small non-coding RNAs which are key post-transcriptional regulators of gene expression. Deregulation of miRNAs is common in human tumorigenesis. We report that miRNA-205 is significantly down-regulated in glioma cell lines and tissue specimens. Ectopic expression of miRNA-205 induces apoptosis, cell cycle arrest, impairs cell viability, clonability and invasive properties of glioma cells. We further demonstrate that miRNA-205 can specifically suppress expression of VEGF-A by directly interacting with the putative miRNA-205 binding site at the 3′-UTR. Identification of VEGF-A as a direct target for miRNA-205 may imply that miRNA-205 is a novel target for glioma therapy. Taken together, the present study for the first time provides evidence that miRNA-205 is a glioma-specific tumor suppressor by targeting VEGF-A.
glioma; miRNA-205; VEGF-A
MicroRNAs (miRNAs) are small, non-coding, endogenous RNA molecules that play important roles in a variety of normal and diseased biological processes by post-transcriptionally regulating the expression of target genes. They can bind to target messenger RNA (mRNA) transcripts of protein-coding genes and negatively control their translation or cause mRNA degradation. miRNAs have been found to actively regulate a variety of cellular processes, including cell proliferation, death, and metabolism. Therefore, their study is crucial for the better understanding of cellular functions in eukaryotes. To better understand the mechanisms of miRNA: mRNA interaction and their cellular functions, it is important to identify the miRNA targets accurately. In this paper, we provide a brief review for the advances in the animal miRNA target prediction methods and available resources to facilitate further study of miRNAs and their functions.
prediction; microRNA; feature selection
MicroRNA (miRNA) is a class of small RNAs of ~22nt which play essential roles in many crucial biological processes and numerous human diseases at post-transcriptional level of gene expression. It has been revealed that miRNA genes tend to be clustered, and the miRNAs organized into one cluster are usually transcribed coordinately. This implies a coordinated regulation mode exerted by clustered miRNAs. However, how the clustered miRNAs coordinate their regulations on large scale gene expression is still unclear.
We constructed the miRNA-transcription factor regulatory network that contains the interactions between transcription factors (TFs), miRNAs and non-TF protein-coding genes, and made a genome-wide study on the regulatory coordination of clustered miRNAs. We found that there are two types of miRNA clusters, i.e. homo-clusters that contain miRNAs of the same family and hetero-clusters that contain miRNAs of various families. In general, the homo-clustered as well as the hetero-clustered miRNAs both exhibit coordinated regulation since the miRNAs belonging to one cluster tend to be involved in the same network module, which performs a relatively isolated biological function. However, the homo-clustered miRNAs show a direct regulatory coordination that is realized by one-step regulation (i.e. the direct regulation of the coordinated targets), whereas the hetero-clustered miRNAs show an indirect regulatory coordination that is realized by a regulation comprising at least three steps (e.g. the regulation on the coordinated targets by a miRNA through a sequential action of two TFs). The direct and indirect regulation target different categories of genes, the former predominantly regulating genes involved in emergent responses, the latter targeting genes that imply long-term effects.
The genomic clustering of miRNAs is closely related to the coordinated regulation in the gene regulatory network. The pattern of regulatory coordination is dependent on the composition of the miRNA cluster. The homo-clustered miRNAs mainly coordinate their regulation rapidly, while the hetero-clustered miRNAs exert control with a delay. The diverse pattern of regulatory coordination suggests distinct roles of the homo-clustered and the hetero-clustered miRNAs in biological processes.
An analysis of amphioxus miRNAs suggests an expansion of miRNAs played a key role in the evolution of chordates to vertebrates
microRNAs (miRNAs) are endogenous small non-coding RNAs that regulate gene expression at the post-transcriptional level. While the number of known human and murine miRNAs is continuously increasing, information regarding miRNAs from other species such as amphioxus remains limited.
We combined Solexa sequencing with computational techniques to identify novel miRNAs in the amphioxus species B. belcheri (Gray). This approach allowed us to identify 113 amphioxus miRNA genes. Among them, 55 were conserved across species and encoded 45 non-redundant mature miRNAs, whereas 58 were amphioxus-specific and encoded 53 mature miRNAs. Validation of our results with microarray and stem-loop quantitative RT-PCR revealed that Solexa sequencing is a powerful tool for miRNA discovery. Analyzing the evolutionary history of amphioxus miRNAs, we found that amphioxus possesses many miRNAs unique to chordates and vertebrates, and these may thus represent key steps in the evolutionary progression from cephalochordates to vertebrates. We also found that amphioxus is more similar to vertebrates than are tunicates with respect to their miRNA phylogenetic histories.
Taken together, our results indicate that Solexa sequencing allows the successful discovery of novel miRNAs from amphioxus with high accuracy and efficiency. More importantly, our study provides an opportunity to decipher how the elaboration of the miRNA repertoire that occurred during chordate evolution contributed to the evolution of the vertebrate body plan.
microRNAs (miRNAs) are a class of small non-coding RNAs which have been recognized as ubiquitous post-transcriptional regulators. The analysis of interactions between different miRNAs and their target genes is necessary for the understanding of miRNAs' role in the control of cell life and death. In this paper we propose a novel data mining algorithm, called HOCCLUS2, specifically designed to bicluster miRNAs and target messenger RNAs (mRNAs) on the basis of their experimentally-verified and/or predicted interactions. Indeed, existing biclustering approaches, typically used to analyze gene expression data, fail when applied to miRNA:mRNA interactions since they usually do not extract possibly overlapping biclusters (miRNAs and their target genes may have multiple roles), extract a huge amount of biclusters (difficult to browse and rank on the basis of their importance) and work on similarities of feature values (do not limit the analysis to reliable interactions).
To overcome these limitations, HOCCLUS2 i) extracts possibly overlapping biclusters, to catch multiple roles of both miRNAs and their target genes; ii) extracts hierarchically organized biclusters, to facilitate bicluster browsing and to distinguish between universe and pathway-specific miRNAs; iii) extracts highly cohesive biclusters, to consider only reliable interactions; iv) ranks biclusters according to the functional similarities, computed on the basis of Gene Ontology, to facilitate bicluster analysis.
Our results show that HOCCLUS2 is a valid tool to support biologists in the identification of context-specific miRNAs regulatory modules and in the detection of possibly unknown miRNAs target genes. Indeed, results prove that HOCCLUS2 is able to extract cohesiveness-preserving biclusters, when compared with competitive approaches, and statistically confirm (at a confidence level of 99%) that mRNAs which belong to the same biclusters are, on average, more functionally similar than mRNAs which belong to different biclusters. Finally, the hierarchy of biclusters provides useful insights to understand the intrinsic hierarchical organization of miRNAs and their potential multiple interactions on target genes.
Post-transcriptional regulation in eukaryotes can be operated through microRNA (miRNAs) mediated gene silencing. MiRNAs are small (18-25 nucleotides) non-coding RNAs that play crucial role in regulation of gene expression in eukaryotes. In insects, miRNAs have been shown to be involved in multiple mechanisms such as embryonic development, tissue differentiation, metamorphosis or circadian rhythm. Insect miRNAs have been identified in different species belonging to five orders: Coleoptera, Diptera, Hymenoptera, Lepidoptera and Orthoptera.
We developed high throughput Solexa sequencing and bioinformatic analyses of the genome of the pea aphid Acyrthosiphon pisum in order to identify the first miRNAs from a hemipteran insect. By combining these methods we identified 149 miRNAs including 55 conserved and 94 new miRNAs. Moreover, we investigated the regulation of these miRNAs in different alternative morphs of the pea aphid by analysing the expression of miRNAs across the switch of reproduction mode. Pea aphid microRNA sequences have been posted to miRBase: http://microrna.sanger.ac.uk/sequences/
Our study has identified candidates as putative regulators involved in reproductive polyphenism in aphids and opens new avenues for further functional analyses.
microRNAs (miRNAs) are small, non-coding RNAs that modulate diverse biological functions through the repression of target genes. miRNA profiling studies have indicated that the levels of miRNAs are altered during normal development and pathogenesis of various diseases, including cancer and cardiovascular disorders. The signaling pathways which control miRNA biogenesis and the mechanisms of regulation, however, are not well understood. Following transcription, mature miRNAs are generated through a series of coordinated processing events mediated by large protein complexes. We recently found that signal transducers of the Transforming Growth Factor β (TGFβ) signaling pathway, the Smads, play a regulatory role in the processing of miRNA in the nucleus. In this review, we summarize the current understanding of the regulation of miRNA biogenesis mediated by the TGFβ signaling pathway.
microRNAs (miRNAs), small noncoding RNAs, are deregulated in several diseases including cancer. miRNAs regulate gene expression at a post-transcriptional level by binding to 5′UTR, coding regions or 3′UTR of messenger RNAs (mRNA), inhibiting mRNA translation or causing mRNA degradation. The same miRNA can have multiple mRNA targets, and the same mRNA can be regulated by various miRNAs.
Recently, seminal contributions by several groups have implicated miRNAs as components of an RNA–RNA language that involves crosstalk between competing endogenous RNAs through a decoy mechanism. We review the studies that described miRNAs as players in a biological decoy activity. miRNAs can either be trapped by competing endogenous RNAs or interact with proteins that have binding sites for mRNAs.
The miRNA decoy functions have implications for the design of therapeutic approaches in human diseases, including specific ways to overcome resistance to drug therapy and future miRNA-based clinical trials design.
mimic; regulation; sponge; therapeutic potential
The most significant recent advance in biomedical research has been the discovery of the~22-nt long class of non-coding RNAs designated as microRNAs (miRNAs). These regulatory RNAs provide a unique level of post-transcriptional gene regulation that modulates a range of fundamental cellular processes. Several viruses, including especially herpesviruses, also encode miRNAs and over 200 viral miRNAs have now been identified. Current evidence indicates that viruses use these miRNAs to manipulate both cellular and viral gene expression. Furthermore, viral infection can exert a profound impact on the cellular miRNA expression profile, and several RNA viruses have been reported to interact directly with cellular miRNAs and/or to use these miRNAs to augment their replication potential. Here we discuss our current knowledge of viral miRNAs and virally-influenced cellular miRNAs, and their relationship to viral infection.
miRNAs; herpesvirus; latency; viral miRNA targets; host-pathogen interactions
MicroRNAs (miRNAs) are small, noncoding RNA molecules that act as post-transcriptional regulators of gene expression. Studies concerning transcriptional regulation of miRNAs have so far concentrated on those located within the intergenic region of the genome and the search for putative promoters, thus leaving open the question of the existence of possible regulatory elements common to all miRNAs including those located in introns of protein coding genes.
In this study, we initially searched for motifs occurring in the area 1000 bp upstream from all miRNAs independent of their genomic location. We discovered a previously unknown sequence motif GANNNNGA that displayed a conserved distribution in the nematode worms Caenorhabditis elegans and Caenorhabditis briggsae. This motif had a peak occurrence at 500 bp upstream, with a sharp drop-off toward the miRNA start site. Further analysis indicated that this motif was locally restricted and not enriched 1000–5000 bp upstream or 0–2000 bp downstream of the miRNA start site. In addition, this motif was observed to be most abundant in the upstream sequences of two important miRNAs, mir-1 and mir-124. This abundance was also conserved in phylogenetically distant species including human and mouse.
The results show that the motif GANNNNGA is conserved close to miRNA precursor start sites, suggesting that it may be involved in miRNA sequence recognition or regulation. This data provides important knowledge for the identification and computational prediction of miRNA sequences.