CiteULike: Group: microRNA - library [913 articles]

Discovering microRNAs from deep sequencing data using miRDeep

Marc Friedländer — 2008-04-08T04:45:36-00:00

Nature Biotechnology, Vol. 26, No. 4., pp. 407-415.

Principles of microRNA regulation of a human cellular signaling network

Qinghua Cui — 2008-08-11T09:56:56-00:00

(18 Dec 2006)

MicroRNAs (miRNAs) are endogenous 22-nucleotide RNAs, which suppress gene expression by selectively binding to the 3-noncoding region of specific message RNAs through base-pairing. Given the diversity and abundance of miRNA targets, miRNAs appear to functionally interact with various components of many cellular networks. By analyzing the interactions between miRNAs and a human cellular signaling network, we found that miRNAs predominantly target positive regulatory motifs, highly connected scaffolds and most downstream network components such as signaling transcription factors, but less frequently target negative regulatory motifs, common components of basic cellular machines and most upstream network components such as ligands. In addition, when an adaptor has potential to recruit more downstream components, these components are more frequently targeted by miRNAs. This work uncovers the principles of miRNA regulation of signal transduction networks and implies a potential function of miRNAs for facilitating robust transitions of cellular response to extracellular signals and maintaining cellular homeostasis.

MicroRNA-directed regulation: to cleave or not to cleave.

Allison C Mallory — 2008-05-28T19:55:00-00:00

Trends in plant science (21 May 2008)

Gene expression is regulated by transcriptional and post-transcriptional pathways, which are crucial for optimizing gene output and for coordinating cellular programs. MicroRNAs (miRNAs) regulate gene expression networks necessary for proper development, cell viability and stress responses. In plants and animals, 20-24-nt miRNAs direct cleavage and translational repression of partially complementary mRNA target transcripts, through conserved ARGONAUTE proteins. In plants, certain miRNAs indirectly regulate developmental programs by instigating the production of small interfering RNAs (siRNAs). In addition, non-cleavable plant miRNA targets sequester miRNAs, thus regulating miRNA availability. This review summarizes the complexities and diversity of plant miRNA-directed gene regulatory mechanisms and highlights the use of miRNAs for the specific knockdown of gene expression in plants.

MicroRNA expression during chick embryo development

Diana Darnell — 2006-10-04T14:41:03-00:00

Developmental Dynamics, Vol. 9999, No. 9999. (2006), NA.

MicroRNAs (miRNAs) are small, abundant, noncoding RNAs that modulate protein abundance by interfering with target mRNA translation or stability. miRNAs are detected in organisms from all domains and may regulate 30% of transcripts in vertebrates. Understanding miRNA function requires a detailed determination of expression, yet this has not been reported in an amniote species. High-throughput whole mount in situ hybridization was performed on chicken embryos to map expression of 135 miRNA genes including five miRNAs that had not been previously reported in chicken. Eighty-four miRNAs were detected before day 5 of embryogenesis, and 75 miRNAs showed differential expression. Whereas few miRNAs were expressed during formation of the primary germ layers, the number of miRNAs detected increased rapidly during organogenesis. Patterns highlighted cell-type, organ or structure-specific expression, localization within germ layers and their derivatives, and expression in multiple cell and tissue types and within sub-regions of structures and tissues. A novel group of miRNAs was highly expressed in most tissues but much reduced in one or a few organs, including the heart. This study presents the first comprehensive overview of miRNA expression in an amniote organism and provides an important foundation for investigations of miRNA gene regulation and function. Developmental Dynamics, 2006. © 2006 Wiley-Liss, Inc.

The Conserved microRNA MiR-8 Tunes Atrophin Levels to Prevent Neurodegeneration in Drosophila

Janina Karres — 2008-06-30T11:46:23-00:00

Cell, Vol. 131, No. 1. (5 October 2007), pp. 136-145.

Summary microRNAs (miRNAs) bind to specific messenger RNA targets to posttranscriptionally modulate their expression. Understanding the regulatory relationships between miRNAs and targets remains a major challenge. Many miRNAs reduce expression of their targets to inconsequential levels. It has also been proposed that miRNAs might adjust target expression to an optimal level. Here we analyze the consequences of mutating the conserved miRNA miR-8 in Drosophila. We identify atrophin as a direct target of miR-8. miR-8 mutant phenotypes are attributable to elevated atrophin activity, resulting in elevated apoptosis in the brain and in behavioral defects. Reduction of atrophin levels in miR-8-expressing cells to below the level generated by miR-8 regulation is detrimental, providing evidence for a "tuning target" relationship between them. Drosophila atrophin is related to the atrophin family of mammalian transcriptional regulators, implicated in the neurodegenerative disorder DRPLA. The regulatory relationship between miR-8 and atrophin orthologs is conserved in mammals.

MicroRNA prediction with a novel ranking algorithm based on random walks

Yunpen Xu — 2008-06-30T09:35:10-00:00

Bioinformatics, Vol. 24, No. 13. (1 July 2008), pp. i50-58.

MicroRNA (miRNAs) play essential roles in post-transcriptional gene regulation in animals and plants. Several existing computational approaches have been developed to complement experimental methods in discovery of miRNAs that express restrictively in specific environmental conditions or cell types. These computational methods require a sufficient number of characterized miRNAs as training samples, and rely on genome annotation to reduce the number of predicted putative miRNAs. However, most sequenced genomes have not been well annotated and many of them have a very few experimentally characterized miRNAs. As a result, the existing methods are not effective or even feasible for identifying miRNAs in these genomes. Aiming at identifying miRNAs from genomes with a few known miRNA and/or little annotation, we propose and develop a novel miRNA prediction method, miRank, based on our new random walks- based ranking algorithm. We first tested our method on Homo sapiens genome; using a very few known human miRNAs as samples, our method achieved a prediction accuracy greater than 95%. We then applied our method to predict 200 miRNAs in Anopheles gambiae, which is the most important vector of malaria in Africa. Our further study showed that 78 out of the 200 putative miRNA precursors encode mature miRNAs that are conserved in at least one other animal species. These conserved putative miRNAs are good candidates for further experimental study to understand malaria infection. Availability: MiRank is programmed in Matlab on Windows platform. The source code is available upon request. Contact: zhang@cse.wustl.edu 10.1093/bioinformatics/btn175

Identification of novel chicken microRNAs and analysis of their genomic organization

Peng Shao — 2008-06-27T14:35:40-00:00

Gene, Vol. 418, No. 1-2. (15 July 2008), pp. 34-40.

MicroRNAs (miRNAs) represent a family of small noncoding RNAs with important regulatory roles in diverse biological processes ranging from cell differentiation to organism development. In chickens, the full set of miRNAs and the expression patterns of miRNAs during development are still poorly understood when compared to the other vertebrates. In this study, we identified 29 novel miRNAs and 140 potential miRNA loci in the chicken genome by combining the experimental and computational analyses. Detailed expression patterns of 49 miRNAs were first characterized by Northern blotting and indicated the cooperativity of the miRNA expression with their function in embryogenesis and organogenesis. Twenty-seven miRNA clusters were systematically evaluated in the chicken genome and diverse expression patterns for closely linked miRNAs were observed. Our results significantly expand the set of known miRNAs in the chicken and provide the basis for understanding the structural and functional evolution of miRNA genes in vertebrates.

Highly sensitive and specific microRNA expression profiling using BeadArray technology

Jing Chen — 2008-06-26T08:38:56-00:00

Nucl. Acids Res. (25 June 2008), gkn387.

We have developed a highly sensitive, specific and reproducible method for microRNA (miRNA) expression profiling, using the BeadArrayTM technology. This method incorporates an enzyme-assisted specificity step, a solid-phase primer extension to distinguish between members of miRNA families. In addition, a universal PCR is used to amplify all targets prior to array hybridization. Currently, assay probes are designed to simultaneously analyse 735 well-annotated human miRNAs. Using this method, highly reproducible miRNA expression profiles were generated with 100-200 ng total RNA input. Furthermore, very similar expression profiles were obtained with total RNA and enriched small RNA species (R2 [≥] 0.97). The method has a 3.5-4 log (105-109 molecules) dynamic range and is able to detect 1.2- to 1.3-fold-differences between samples. Expression profiles generated by this method are highly comparable to those obtained with RT-PCR (R2 = 0.85-0.90) and direct sequencing (R = 0.87-0.89). This method, in conjunction with the 96-sample array matrix should prove useful for high-throughput expression profiling of miRNAs in large numbers of tissue samples. 10.1093/nar/gkn387

Functionally distinct regulatory RNAs generated by bidirectional transcription and processing of microRNA loci

David Tyler — 2008-01-05T12:36:45-00:00

Genes Dev., Vol. 22, No. 1. (1 January 2008), pp. 26-36.

Many microRNA (miRNA) loci exhibit compelling hairpin structures on both sense and antisense strands; however, the possibility that a miRNA gene might produce functional species from its antisense strand has not been examined. We report here that antisense transcription of the Hox miRNA locus mir-iab-4 generates the novel pre-miRNA hairpin mir-iab-8, which is then processed into endogenous mature miRNAs. Sense and antisense iab-4/iab-8 miRNAs are functionally distinguished by their distinct domains of expression and targeting capabilities. We find that miR-iab-8-5p, like miR-iab-4-5p, is also relevant to Hox gene regulation. Ectopic mir-iab-8 can strongly repress the Hox genes Ultrabithorax and abdominal-A via extensive arrays of conserved target sites, and can induce a dramatic homeotic transformation of halteres into wings. We generalize the antisense miRNA principle by showing that several other loci in both invertebrates and vertebrates are endogenously processed on their antisense strands into mature miRNAs with distinct seeds. These findings demonstrate that antisense transcription and processing contributes to the functional diversification of miRNA genes. 10.1101/gad.1615208

The regulatory activity of microRNA(*) species has substantial influence on microRNA and 3' UTR evolution.

Katsutomo Okamura — 2008-04-03T15:35:49-00:00

Nature structural & molecular biology (30 March 2008)

During microRNA (miRNA) biogenesis, one strand of a approximately 21-22-nucleotide RNA duplex is preferentially selected for entry into a silencing complex. The other strand, known as the miRNA(*) species, has typically been assumed to be a carrier strand. Here we show that, although Drosophila melanogaster miRNA(*) species are less abundant than their partners, they are often present at physiologically relevant levels and can associate with Argonaute proteins. Comparative genomic analyses revealed that >40% of miRNA(*) sequences resist nucleotide divergence across Drosophilid evolution, and at least half of these well-conserved miRNA(*) species select for conserved 3' untranslated region seed matches well above background noise. Finally, we validated the inhibitory activity of miRNA(*) species in both cultured cells and transgenic animals. These data broaden the reach of the miRNA regulatory network and suggest an important mechanism that diversifies miRNA function during evolution.

Functional screening identifies miR-315 as a potent activator of Wingless signaling

Serena Silver — 2008-02-11T02:36:04-00:00

Proceedings of the National Academy of Sciences, Vol. 104, No. 46. (13 November 2007), pp. 18151-18156.

The existence of vast regulatory networks mediated by microRNAs (miRNAs) suggests broad potential for miRNA dysfunction to contribute to disease. However, relatively few miRNAtarget interactions are likely to make detectable contributions to phenotype, and effective strategies to identify these few interactions are currently wanting. We hypothesized that signaling cascades represent critical points of susceptibility to miRNA dysfunction, and we developed a strategy to test this theory by using quantitative cell-based screens. Here we report a screen for miRNAs that affect the Wingless (Wg) pathway, a conserved pathway that regulates growth and tissue specification. This process identified ectopic miR-315 as a potent and specific activator of Wg signaling, an activity that we corroborated in transgenic animals. This miR-315 activity was mediated by direct inhibition of Axin and Notum, which encode essential, negatively acting components of the Wg pathway. Genetic interaction tests substantiated both of these genes as key functional targets of miR-315. The ability of ectopic miR-315 to activate Wg signaling was not a trivial consequence of predicted miRNAtarget relationships because other miRNAs with conserved sites in the Axin 3' UTR neither activated Wg outputs nor inhibited an Axin sensor. In summary, activity-based screening can selectively identify miRNAs whose deregulation can lead to interpretable phenotypic consequences. 10.1073/pnas.0706673104

Identification of human microRNA targets from isolated argonaute protein complexes.

M Beitzinger — 2008-06-24T11:32:53-00:00

RNA biology, Vol. 4, No. 2. (June 2007), pp. 76-84.

MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that regulate gene expression on the level of translation and/or mRNA stability. Mammalian miRNAs associate with members of the Argonaute (Ago) protein family and bind to partially complementary sequences in the 3' untranslated region (UTR) of specific target mRNAs. Computer algorithms based on factors such as free binding energy or sequence conservation have been used to predict miRNA target mRNAs. Based on such predictions, up to one third of all mammalian mRNAs seem to be under miRNA regulation. However, due to the low degree of complementarity between the miRNA and its target, such computer programs are often imprecise and therefore not very reliable. Here we report the first biochemical identification approach of miRNA targets from human cells. Using highly specific monoclonal antibodies against members of the Ago protein family, we co-immunoprecipitate Ago-bound mRNAs and identify them by cloning. Interestingly, most of the identified targets are also predicted by different computer programs. Moreover, we randomly analyzed six different target candidates and were able to experimentally validate five as miRNA targets. Our data clearly indicate that miRNA targets can be experimentally identified from Ago complexes and therefore provide a new tool to directly analyze miRNA function.

Control of protein synthesis and mRNA degradation by microRNAs

Jidong Liu — 2008-04-10T11:28:03-00:00

Current Opinion in Cell Biology, Vol. 20, No. 2. (April 2008), pp. 214-221.

MicroRNAs represent a large family of non-coding small RNAs that function as the major endogenous triggers for RNA interference. Hundreds of microRNAs have been identified through small RNA cloning, bioinformatic predictions, and high-throughput pyrosequencing. They are believed to suppress gene expression through post-transcriptional regulation via either translational repression or mRNA turnover. Over one third of human genes are predicted targets for microRNAs. However, even after extensive studies, the function of microRNAs and the precise mechanism by which they suppress gene expression remain elusive. Although controversy remains, recent advances have shined new light on how microRNAs regulate their targets. A better understanding of the mechanism should facilitate studies of their function.

Computational Modeling of Post-Transcriptional Gene Regulation by MicroRNAs.

Raya Khanin — 2008-03-13T14:57:51-00:00

J Comput Biol (11 March 2008)

MicroRNAs (miRNAs) have recently emerged as a new complex layer of gene regulation. MiRNAs act post-transcriptionally, influencing the stability, compartmentalization, and translation of their target mRNAs. Computational efforts to understand the post-transcriptional gene regulation by miRNAs have been focused on the target prediction tools, while quantitative kinetic models of gene regulation by miRNAs have so far largely been overlooked. We here develop a kinetic model of post-transcriptional gene regulation by miRNAs, focusing on the miRNAs' effect on increasing the target mRNAs degradation rates. The model is fitted to a temporal microarray dataset where human mRNAs are measured upon transfection with a specific miRNA (miRNA124a). The proposed model exhibits good fit with many target mRNA profiles, indicating that such type of models can be used for studying post-transcriptional gene regulation by miRNA. In particular, the proposed kinetic model can be used for quantifying the miRNA-mediated effects on its targets in the miRNA mis-expression experiments. The model makes an experimentally verifiable prediction of the miRNA124a decay rate, quantifies the miRNA-mediated effect on the target mRNAs degradation, and yields a good correspondence between the inferred and experimentally measured decay rates of human target mRNAs.

Inter- and intra-combinatorial regulation by transcription factors and microRNAs

Yiming Zhou — 2007-10-31T09:34:56-00:00

BMC Genomics, Vol. 8 (30 October 2007), 396.

Regulation of microRNA Expression: the Hypoxic Component

Ritu Kulshreshtha — 2008-06-23T13:47:05-00:00

Cell Cycle, Vol. 6, No. 12. (15 June 2007), pp. 1426-1431.

microRNAs are involved in a wide variety of normal and pathological cellular processes, including tumorigenic transformation. Despite significant progress made towards understanding their mechanisms of action, much less is known about the regulation of expression of specific microRNAs. Recent reports have established a link between hypoxia, a key feature of the tumor microenvironment, and a group of microRNAs. Select members of this group seem to affect apoptotic signaling in a hypoxic environment and are also predicted to target genes of critical importance for tumor biology. Interestingly, most hypoxia-induced microRNAs are also overexpressed in human cancers, suggesting a role in tumorigenesis. We hereby discuss the known and predicted regulators of microRNA expression and approaches for expanding this fledgling research area.

MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals.

J Tsang — 2007-12-03T19:19:00-00:00

Mol Cell, Vol. 26, No. 5. (8 June 2007), pp. 753-767.

MicroRNAs (miRNAs) are regulatory molecules that participate in diverse biological processes in animals and plants. While thousands of mammalian genes are potentially targeted by miRNAs, the functions of miRNAs in the context of gene networks are not well understood. Specifically, it is unknown whether miRNA-containing networks have recurrent circuit motifs, as has been observed in regulatory networks of bacteria and yeast. Here we develop a computational method that utilizes gene expression data to show that two classes of circuits-corresponding to positive and negative transcriptional coregulation of a miRNA and its targets-are prevalent in the human and mouse genomes. Additionally, we find that neuronal-enriched miRNAs tend to be coexpressed with their target genes, suggesting that these miRNAs could be involved in neuronal homeostasis. Our results strongly suggest that coordinated transcriptional and miRNA-mediated regulation is a recurrent motif to enhance the robustness of gene regulation in mammalian genomes.

Endogenous human microRNAs that suppress breast cancer metastasis

Sohail Tavazoie — 2008-01-10T06:08:57-00:00

Nature, Vol. 451, No. 7175., pp. 147-152.

Identification of transcription factor and microRNA binding sites in responsible to fetal alcohol syndrome

Guohua Wang — 2008-06-23T10:32:54-00:00

BMC Genomics, Vol. 9, No. Suppl 1. (2008)

This is a first report, using our MotifModeler informatics program, to simultaneously identify transcription factor (TF) and microRNA (miRNA) binding sites from gene expression microarray data. Based on the assumption that gene expression is controlled by combinatorial effects of transcription factors binding in the 5'-upstream regulatory region and miRNAs binding in the 3'-untranslated region (3'-UTR), we developed a model for (1) predicting the most influential cis-acting elements under a given biological condition, and (2) estimating the effects of those elements on gene expression levels. The regulatory regions, TF and miRNA, which mediate the differential genes expression in fetal alcohol syndrome were unknown; microarray data from alcohol exposure paradigm was used. The model predicted strong inhibitory effects of 5' cis-acting elements and stimulatory effects of 3'-UTR under alcohol treatment. Current predictive model derived a key hypothesis for the first time a novel role of miRNAs in gene expression changes associated with abnormal mouse embryo development after alcohol exposure. This suggests that disturbance of miRNA functions may contribute to the alcohol-induced developmental deficiencies.

Hematopoietic Lineage Commitment: miRNAs Add Specificity to a Widely Expressed Transcription Factor

Paloma García — 2008-06-23T10:10:43-00:00

Developmental Cell, Vol. 14, No. 6. (10 June 2008), pp. 815-816.

MicroRNAs are important regulators of normal and malignant hematopoiesis. A paper by Lu et al. in this issue of Developmental Cell demonstrates how one microRNA, miR-150, plays a critical role in commitment of the erythroid-megakaryocyte progenitor by modulating the level of the widely expressed transcription factor MYB (or c-Myb).

Modulation of ionizing radiation-induced apoptosis by bantam microRNA in Drosophila

Burnley Jaklevic — 2008-06-23T10:04:03-00:00

Developmental Biology, Vol. In Press, Corrected Proof

In Drosophila, heterozygosity in the pro-apoptotic gene hid significantly reduces apoptosis that is induced by ionizing radiation (IR). Therefore, mechanisms that regulate Hid levels can potentially contribute to life-or-death decision of an irradiated cell. 3'UTR of hid mRNA contains 5 potential binding sites for bantam microRNA. Ectopic expression of ban attenuated apoptosis that results from ectopic expression of hid but the significance of this regulation under physiological conditions remained to be investigated. We report here that ban is needed to limit IR-induced apoptosis in larval imaginal discs. Using tubulin-EGFP ban sensors with ban consensus sequences in the 3'UTR, we find that EGFP decreases following IR, indicating that IR activates ban. Likewise, a tubulin-EGFP reporter with hid-3'UTR is repressed in irradiated discs and this repression requires ban consensus sites in the hid 3'UTR. ban mutant larvae show increased sensitivity to killing by IR, which is suppressed by a mutation in hid. These results can fit into a model in which IR activates ban and ban represses hid to limit IR-induced apoptosis. miRNAs have been shown previously to be induced by radiation but this is the first report that a miRNA is functionally important for radiation responses.

Everything you wanted to know about small RNA but were afraid to ask

Scott Boyd — 2008-04-21T17:31:41-00:00

Laboratory Investigation, Vol. aop, No. current.

Individual mRNA expression profiles reveal the effects of specific microRNAs

Amit Arora — 2008-05-17T12:38:09-00:00

Genome Biology, Vol. 9 (16 May 2008), R82.

MicroRNA regulation of messenger-like noncoding RNAs: a network of mutual microRNA control

Yi Zhao — 2008-06-04T14:14:19-00:00

Trends in Genetics, Vol. In Press, Corrected Proof

Metazoan microRNAs (miRNAs) are commonly encoded by primary mRNA-like characteristics (mlRNAs). To investigate whether mlRNAs are subject to miRNA control, we compared the expression of mlRNAs to that of tissue-specific miRNAs. We show that, like mRNAs, the expression levels of predicted mlRNA targets are significantly reduced in tissues where a targeting miRNA is expressed. On the basis of these results, we describe a potential network for posttranscriptional miRNA-miRNA control.

Conservation of small RNA pathways in platypus

Elizabeth Murchison — 2008-05-12T17:33:33-00:00

Genome Res. (7 May 2008), gr.073056.107.

Small RNA pathways play evolutionarily conserved roles in gene regulation and defense from parasitic nucleic acids. The character and expression patterns of small RNAs show conservation throughout animal lineages, but specific animal clades also show variations on these recurring themes, including species-specific small RNAs. The monotremes, with only platypus and four species of echidna as extant members, represent the basal branch of the mammalian lineage. Here, we examine the small RNA pathways of monotremes by deep sequencing of six platypus and echidna tissues. We find that highly conserved microRNA species display their signature tissue-specific expression patterns. In addition, we find a large rapidly evolving cluster of microRNAs on platypus chromosome X1, which is unique to monotremes. Platypus and echidna testes contain a robust Piwi-interacting (piRNA) system, which appears to be participating in ongoing transposon defense. 10.1101/gr.073056.107

Small RNAs tell big stories in Whistler

Amy Seila — 2008-06-02T16:02:05-00:00

Nat Cell Biol, Vol. 10, No. 6. (June 2008), pp. 630-633.

Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis

Yong Zhao — 2005-06-12T20:39:42-00:00

Nature (12 June 2005)

microRNAs and the immune response

Mark Lindsay — 2008-06-02T08:48:45-00:00

Trends in Immunology, Vol. In Press, Corrected Proof

microRNA (miRNA)-mediated RNA interference has been identified as a novel mechanism that regulates protein expression at the translational level. Recent publications have provided compelling evidence that a range of miRNAs are involved in the regulation of immunity, including the development and differentiation of B and T cells, proliferation of monocytes and neutrophils, antibody switching and the release of inflammatory mediators. In this review, we examine what is presently known of the function and mechanism of action of these miRNAs in the regulation of the innate and acquired immune response.

Decoding ARE-mediated decay: is microRNA part of the equation?

Christopher von Roretz — 2008-05-30T15:33:47-00:00

J. Cell Biol., Vol. 181, No. 2. (21 April 2008), pp. 189-194.

Messenger ribonucleic acids (mRNAs) containing adenine/uridine-rich elements (AREs) in their 3' untranslated region are particularly labile, allowing for the regulation of expression for growth factors, oncoproteins, and cytokines. The regulators, effectors, and location of ARE-mediated decay (AMD) have been investigated by many groups in recent years, and several links have been found between AMD and microRNA-mediated decay. We highlight these similarities, along with recent advances in the field of AMD, and also mention how there is still much left unknown surrounding this specialized mode of mRNA decay. 10.1083/jcb.200712054

Members of the miRNA-200 family regulate olfactory neurogenesis.

PS Choi — 2008-03-06T13:10:42-00:00

Neuron, Vol. 57, No. 1. (10 January 2008), pp. 41-55.

MicroRNAs (miRNAs) are highly expressed in vertebrate neural tissues, but the contribution of specific miRNAs to the development and function of different neuronal populations is still largely unknown. We report that miRNAs are required for terminal differentiation of olfactory precursors in both mouse and zebrafish but are dispensable for proper function of mature olfactory neurons. The repertoire of miRNAs expressed in olfactory tissues contains over 100 distinct miRNAs. A subset, including the miR-200 family, shows high olfactory enrichment and expression patterns consistent with a role during olfactory neurogenesis. Loss of function of the miR-200 family phenocopies the terminal differentiation defect observed in absence of all miRNA activity in olfactory progenitors. Our data support the notion that vertebrate tissue differentiation is controlled by conserved subsets of organ-specific miRNAs in both mouse and zebrafish and provide insights into control mechanisms underlying olfactory differentiation in vertebrates.

NONCODING RNAS IN THE MAMMALIAN CENTRAL NERVOUS SYSTEM.

Xinwei Cao — 2006-07-06T14:36:10-00:00

Annu Rev Neurosci, Vol. 29 (21 July 2006), pp. 77-103.

The central nervous system (CNS) is arguably one of the most complex systems in the universe. To understand the CNS, scientists have investigated a variety of molecules, including proteins, lipids, and various small molecules. However, one large class of molecules, noncoding RNAs (ncRNAs), has been relatively unexplored. ncRNAs function directly as structural, catalytic, or regulatory molecules rather than serving as templates for protein synthesis. The increasing variety of ncRNAs being identified in the CNS suggests a strong connection between the biogenesis, dynamics of action, and combinatorial regulatory potential of ncRNAs and the complexity of the CNS. In this review, we give an overview of the diversity and abundance of ncRNAs before delving into specific examples that illustrate their importance in the CNS. In particular, we cover recent evidence for the roles of microRNAs, small nucleolar RNAs, retrotransposons, the NRSE small modulatory RNA, and BC1/BC200 in the CNS. Finally, we speculate why ncRNAs are well adapted to improving organism-environment interactions.

The neuronal microRNA system

Kenneth Kosik — 2006-11-20T22:53:28-00:00

Nature Reviews Neuroscience, Vol. 7, No. 12., pp. 911-920.

The MicroRNA miR-1 Regulates a MEF-2-Dependent Retrograde Signal at Neuromuscular Junctions

David Simon — 2008-05-30T09:43:29-00:00

Cell, Vol. 133, No. 5. (30 May 2008), pp. 903-915.

Summary We show that miR-1, a conserved muscle-specific microRNA, regulates aspects of both pre- and postsynaptic function at C. elegans neuromuscular junctions. miR-1 regulates the expression level of two nicotinic acetylcholine receptor (nAChR) subunits (UNC-29 and UNC-63), thereby altering muscle sensitivity to acetylcholine (ACh). miR-1 also regulates the muscle transcription factor MEF-2, which results in altered presynaptic ACh secretion, suggesting that MEF-2 activity in muscles controls a retrograde signal. The effect of the MEF-2-dependent retrograde signal on secretion is mediated by the synaptic vesicle protein RAB-3. Finally, acute activation of levamisole-sensitive nAChRs stimulates MEF-2-dependent transcriptional responses and induces the MEF-2-dependent retrograde signal. We propose that miR-1 refines synaptic function by coupling changes in muscle activity to changes in presynaptic function.

Widespread Translational Inhibition by Plant miRNAs and siRNAs

Peter Brodersen — 2008-05-16T09:08:52-00:00

Science (15 May 2008), 1159151.

High complementarity between plant miRNAs and their mRNA targets is thought to cause silencing prevalently by endonucleolytic cleavage. We have isolated Arabidopsis mutants defective in miRNA action. Their analysis provides evidence that plant miRNA-guided silencing has a widespread translational inhibitory component that is genetically separable from endonucleolytic cleavage. We further show that the same is true of silencing mediated by short interfering (si)RNA populations. Translational repression is effected in part by the ARGONAUTE proteins AGO1 and AGO10. It also requires the activity of the microtubule-severing enzyme katanin, implicating cytoskeleton dynamics in miRNA action as recently suggested from animal studies. Also as in animals, the decapping component VCS/Ge-1 is required for translational repression by miRNAs, suggesting that the underlying mechanisms in the two kingdoms are related. 10.1126/science.1159151

Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model

Kimberly Stark — 2008-05-29T11:11:33-00:00

Nat Genet, Vol. 40, No. 6. (June 2008), pp. 751-760.

Identification and characteristics of microRNAs from Bombyx mori

Ping He — 2008-05-28T14:41:55-00:00

BMC Genomics, Vol. 9, No. 1. (2008)

BACKGROUND:MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression by targeting messenger RNAs (mRNAs) and causing mRNA cleavage or translation blockage. Of the 355 Arthropod miRNAs that have been identified, only 21 are B. mori miRNAs that were predicted computationally; of these, only let-7 has been confirmed by Northern blotting.RESULTS:Combining a computational method based on sequence homology searches with experimental identification based on microarray assays and Northern blotting, we identified 46 miRNAs, an additional 21 plausible miRNAs, and a novel small RNA in B. mori. The latter, bmo-miR-100-like, was identified using the known miRNA aga-miR-100 as a probe; bmo-miR-100-like was detected by microarray assay and Northern blotting, but its precursor sequences did not fold into a hairpin structure. Among these identified miRNAs, we found 12 pairs of miRNAs and miRNA*s. Northern blotting revealed that some B. mori miRNA genes were expressed only during specific stages, indicating that B. mori miRNA genes (e.g., bmo-miR-277) have developmentally regulated patterns of expression. We identified two miRNA gene clusters in the B. mori genome. bmo-miR-2b, which is found in the gene cluster bmo-miR-2a-1 / bmo-miR-2a-1* / bmo-miR-2a-2/ bmo-miR-2b / bmo-miR-13a* / bmo-miR-13b, encodes a newly identified member of the mir-2 family. Moreover, we found that methylation can increase the sensitivity of a DNA probe used to detect a miRNA by Northern blotting. Functional analysis revealed that 11 miRNAs may regulate 13 B. mori orthologs of the 25 known Drosophila miRNA-targeted genes according to the functional conservation. We predicted the binding sites on the 1671 3'UTR of B. mori genes; 547 targeted genes, including 986 target sites, were predicted. Of these target sites, 338 had perfect base pairing to the seed region of 43 miRNAs. From the predicted genes, 61 genes, each of them with multiple predicted target sites, should be considered excellent candidates for future functional studies. Biological classification of predicted miRNA targets showed that "binding", "catalytic activity" and "physiological process" were over-represented for the predicted genes.CONCLUSIONS:Combining computational predictions with microarray assays, we identified 46 B. mori miRNAs, 13 of which were miRNA*s. We identified a novel small RNA and 21 plausible B. mori miRNAs that could not be located in the available B. mori genome, but which could be detected by microarray. Thirteen and 547 target genes were predicted according to the functional conservation and binding sites, respectively. Identification of miRNAs in B. mori, particularly those that are developmentally regulated, provides a foundation for subsequent functional studies.

A microRNA catalog of the developing chicken embryo identified by a deep sequencing approach

Evgeny Glazov — 2008-05-28T10:27:47-00:00

Genome Res. (9 May 2008), gr.074740.107.

MicroRNA (miRNA) and other types of small regulatory RNAs play a crucial role in the regulation of gene expression in eukaryotes. Several distinct classes of small regulatory RNAs have been discovered in recent years. To extend the repertoire of small regulatory RNAs characterized in chickens we used a deep sequencing approach developed by Solexa (now Illumina Inc.). We sequenced three small RNA libraries prepared from different developmental stages of the chicken embryo (days five, seven, and nine) to produce over 9.5 million short sequence reads. We developed a bioinformatics pipeline to distinguish authentic mature miRNA sequences from other classes of small RNAs and short RNA fragments represented in the sequencing data. Using this approach we detected almost all of the previously known chicken miRNAs and their respective miRNA* sequences. In addition we discovered 449 new chicken miRNAs including 88 miRNA candidates. Of these, 430 miRNAs appear to be specific to the avian lineage. Another six new miRNAs had evidence of evolutionary conservation in at least one vertebrate species outside of the bird lineage. The remaining 13 putative miRNAs appear to represent chicken orthologs of known vertebrate miRNAs. We discovered 39 additional putative miRNA candidates originating from miRNA generating intronic sequences known as mirtrons. 10.1101/gr.074740.107

Deep Sequencing of Chicken microRNAs

Joan Burnside — 2008-04-23T07:16:18-00:00

BMC Genomics, Vol. 9 (22 April 2008), 185.

MicroRNA switches in Trypanosoma brucei

Bibekanand Mallick — 2008-05-28T08:51:41-00:00

Biochemical and Biophysical Research Communications, Vol. In Press, Uncorrected Proof

Trypanosoma brucei develops chronic infection in mammalian hosts due to a sophisticated strategy of antigenic variation of variant surface glycoprotein (VSG) coat to escape antibody-mediated lysis. MicroRNAs are a class of non-coding RNAs with presumed post-transcriptional regulatory activity. Homology based informatic approach is used to identify the microRNA (miRNA) genes of T. brucei and their target mRNAs. Our observation reveals a set of microRNAs targeting mRNAs corresponding to VSGs. Further, a number of miRNA hairpins have been found in clusters of multiple identical copies. The target proteins, 20S proteosome, GM6 and GRESAG 4.2 corresponding to these clustered miRNAs play essential role in trypanosomiasis. These snippets can act as genetic switches modulating host-parasite interaction and provide useful clue toward treatment of trypanosomiasis.

On the relationship between GC content and the number of predicted microRNA binding sites by MicroInspector.

N Davis — 2008-05-21T15:47:35-00:00

Computational biology and chemistry, Vol. 32, No. 3. (June 2008), pp. 222-226.

MicroRNA GC content and length is believed to play a role in the prediction of putative microRNA targets. MicroInspector was evaluated to determine the extent to which these characteristics of microRNAs play a role in binding site predictive accuracy. A strong bias towards under predicting the number of expected bindings sites for low GC content sequences was observed, especially for microRNAs with <50% GC content. Researchers working with organisms with unusually low GC content should be aware of this bias.

MicroRNA expression profiles classify human cancers

Jun Lu — 2005-06-08T20:26:28-00:00

Nature, Vol. 435, No. 7043., pp. 834-838.

Using expression profiling data to identify human microRNA targets

Jim Huang — 2007-11-29T18:47:18-00:00

Nat Meth, Vol. 4, No. 12. (December 2007), pp. 1045-1049.

miRiad Roles for the miR-17-92 Cluster in Development and Disease

Joshua Mendell — 2008-04-23T14:51:34-00:00

Cell, Vol. 133, No. 2. (18 April 2008), pp. 217-222.

MicroRNAs (miRNAs) encoded by the miR-17-92 cluster and its paralogs are known to act as oncogenes. Expression of these miRNAs promotes cell proliferation, suppresses apoptosis of cancer cells, and induces tumor angiogenesis. New work reveals essential functions for these miRNAs not only in tumor formation but also during normal development of the heart, lungs, and immune system.

A scoring matrix approach to detecting miRNA target sites

Simon Moxon — 2008-03-31T17:46:38-00:00

Algorithms for Molecular Biology, Vol. 3 (31 March 2008), 3.

Piecing Together the Mosaic of Early Mammalian Development through MicroRNAs

Adriana Blakaj — 2008-04-04T13:04:59-00:00

J. Biol. Chem., Vol. 283, No. 15. (11 April 2008), pp. 9505-9508.

The microRNA (miRNA) pathway represents an integral component of the gene regulation circuitry that controls development. In recent years, the role of miRNAs in embryonic stem (ES) cells and mammalian embryogenesis has begun to be explored. A few dozens of miRNAs expressed in mammalian ES cells, either exclusively or nonexclusively, have been cloned. The overall role of miRNAs in ES cells and embryonic development has been assessed by examining the effect of knocking out Dicer, an RNase III enzyme required for miRNA and small interfering RNA biogenesis, as well as DGCR8, a nuclear protein specifically involved in miRNA biogenesis. In addition, the role of a cluster of miRNAs specifically expressed in ES cells, the miR-290295 group, has been investigated by the knock-out approach. These analyses have revealed the crucial role of miRNAs in ES cell differentiation, lineage specification, and organogenesis, especially neurogenesis and cardiogenesis. Systematic investigation of the role of miRNAs in ES cells and embryos will allow us to find missing pieces of the mosaic of early development. 10.1074/jbc.R800002200

Multilevel Regulation of Gene Expression by MicroRNAs

Eugene Makeyev — 2008-03-28T15:03:59-00:00

Science, Vol. 319, No. 5871. (28 March 2008), pp. 1789-1790.

MicroRNAs (miRNAs) are [~]22-nucleotide-long noncoding RNAs that normally function by suppressing translation and destabilizing messenger RNAs bearing complementary target sequences. Some miRNAs are expressed in a cell- or tissue-specific manner and may contribute to the establishment and/or maintenance of cellular identity. Recent studies indicate that tissue-specific miRNAs may function at multiple hierarchical levels of gene regulatory networks, from targeting hundreds of effector genes incompatible with the differentiated state to controlling the levels of global regulators of transcription and alternative pre-mRNA splicing. This multilevel regulation may allow individual miRNAs to profoundly affect the gene expression program of differentiated cells. 10.1126/science.1152326

Gene Regulation by Transcription Factors and MicroRNAs

Oliver Hobert — 2008-03-28T15:00:47-00:00

Science, Vol. 319, No. 5871. (28 March 2008), pp. 1785-1786.

The properties of a cell are determined by the genetic information encoded in its genome. Understanding how such information is differentially and dynamically retrieved to define distinct cell types and cellular states is a major challenge facing molecular biology. Gene regulatory factors that control the expression of genomic information come in a variety of flavors, with transcription factors and microRNAs representing the most numerous gene regulatory factors in multicellular genomes. Here, I review common principles of transcription factor and microRNA-mediated gene regulatory events and discuss conceptual differences in how these factors control gene expression. 10.1126/science.1151651

The Effect of Central Loops in miRNA:MRE Duplexes on the Efficiency of miRNA-Mediated Gene Regulation.

W Ye — 2008-03-18T02:56:30-00:00

PLoS ONE, Vol. 3, No. 3. (2008)

MicroRNAs (miRNAs) guide posttranscriptional repression of mRNAs. Hundreds of miRNAs have been identified but the target identification of mammalian mRNAs is still a difficult task due to a poor understanding of the interaction between miRNAs and the miRNA recognizing element (MRE). In recent research, the importance of the 5' end of the miRNA:MRE duplex has been emphasized and the effect of the tail region addressed, but the role of the central loop has largely remained unexplored. Here we examined the effect of the loop region in miRNA:MRE duplexes and found that the location of the central loop is one of the important factors affecting the efficiency of gene regulation mediated by miRNAs. It was further determined that the addition of a loop score combining both location and size as a new criterion for predicting MREs and their cognate miRNAs significantly decreased the false positive rates and increased the specificity of MRE prediction.

MicroRNA expression profiling of the developing murine molar tooth germ and the developing murine submandibular salivary gland

Anne-Marthe Jevnaker — 2008-03-19T10:16:34-00:00

Archives of Oral Biology, Vol. In Press, Corrected Proof

Using microarrays, miRNA expression profiles have been established at selected times during development (E15.5, P0 and P5) of the murine first molar mandibular tooth germ and the right submandibular salivary gland (E15.5, P0, P5 and P25). Microarray data was validated using real-time PCR, also facilitating RT-PCR profiling of nine selected miRNAs. In general, good agreement between microarray data and real-time PCR data was found. Further, miRNA expression profiles of foetal and adult liver were also investigated, and found to agree with published data. In tooth germ and salivary gland up to 88 different miRNAs were detected. In all tissues examined miRNA expression was highly dynamic; miRNA profiles changing extensively with time of development. Additionally, the expression of some miRNAs was tissue-specific. Bioinformatic analysis of clusters of miRNAs was attempted using the miRGate software, the results suggesting miRNAs to be involved in the regulation of essential developmental processes, e.g., epithelical cell proliferation, mesodermal cell fate determination and salivary gland morphogenesis.

Selective Blockade of MicroRNA Processing by Lin-28.

Srinivas R Viswanathan — 2008-02-25T08:32:02-00:00

Science (21 February 2008)

MicroRNAs (miRNAs) play critical roles in development, and dysregulation of miRNA expression has been observed in human malignancies. Recent evidence suggests that the processing of several primary miRNA transcripts (pri-miRNAs) is blocked post-transcriptionally in embryonic stem (ES) cells, embryonal carcinoma (EC) cells, and primary tumors. Here we show that Lin-28, a developmentally regulated RNA-binding protein, selectively blocks the processing of pri-let-7 miRNAs in embryonic cells. Using in vitro and in vivo studies, we demonstrate that Lin-28 is necessary and sufficient for blocking Microprocessor-mediated cleavage of pri-let-7 miRNAs. Our results identify Lin-28 as a negative regulator of miRNA biogenesis and suggest that Lin-28 may play a central role in blocking miRNA-mediated differentiation in stem cells and certain cancers.