CiteULike: maralena's library [489 articles]

PathCluster: a framework for gene set-based hierarchical clustering.

Tae-Min Kim — 2008-07-18T07:47:02-00:00

Bioinformatics (Oxford, England) (15 July 2008)

MOTIVATION: Gene clustering and gene set-based functional analysis are widely used for the analysis of expression profiles. The development of a comprehensive method jointly combining the two methods would allow for greater biological insights. RESULTS: We developed a software package, PathCluster for gene set-based clustering via an agglomerative hierarchical clustering algorithm. The distances between predefined gene sets are illustrated in a dendrogram in which the relationships between gene sets can be visually assessed. Valuable biological insights can be obtained according to the type of gene sets, e.g. coordinated action of molecular functions (functional gene sets) and putative motif syn-ergy (promoter gene set) in a biological process. The combined use of gene sets further enables the interrogation of different biological themes and their putative relationships, such as function-versus-regulatory motif or drug-versus-function. PathCluster can also be used for knowledge-based sample partitioning or class categoriza-tion for clinical purposes. With extended applicability, PathCluster will facilitate the gleaning of meaningful biological insights and test-able hypotheses in the contexts of given expression profiles. AVAILABILITY: PathCluster executable files can be freely downloaded at http://www.systemsbiology.co.kr/PathCluster/. CONTACT: yejun@catholic.ac.kr.

Primary microRNA transcript retention at sites of transcription leads to enhanced microRNA production.

JM Pawlicki — 2008-07-17T09:26:43-00:00

The Journal of cell biology, Vol. 182, No. 1. (14 July 2008), pp. 61-76.

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.

Functional organisation of Escherichia coli transcriptional regulatory network

Agustino Martínez-Antonio — 2008-07-11T16:12:07-00:00

Journal of Molecular Biology, Vol. 381, No. 1. (1 August 2008), pp. 238-247.

Taking advantage of available functional data associated with 115 transcription and 7 sigma factors, we have performed a structural analysis of the regulatory network of Escherichia coli. While the mode of regulatory interaction between transcription factors (TFs) is predominantly positive, TFs are frequently negatively autoregulated. Furthermore, feedback loops, regulatory motifs and regulatory pathways are unevenly distributed in this network. Short pathways, multiple feed-forward loops and negative autoregulatory interactions are particularly predominant in the subnetwork controlling metabolic functions such as the use of alternative carbon sources. In contrast, long hierarchical cascades and positive autoregulatory loops are overrepresented in the subnetworks controlling developmental processes for biofilm and chemotaxis. We propose that these long transcriptional cascades coupled with regulatory switches (positive loops) for external sensing enable the coexistence of multiple bacterial phenotypes. In contrast, short regulatory pathways and negative autoregulatory loops enable an efficient homeostatic control of crucial metabolites despite external variations. TFs at the core of the network coordinate the most basic endogenous processes by passing information onto multi-element circuits. Transcriptional expression data support broader and higher transcription of global TFs compared to specific ones. Global regulators are also more broadly conserved than specific regulators in bacteria, pointing to varying functional constraints.

Mouse let-7 miRNA populations exhibit RNA editing that is constrained in the 5'-seed/cleavage/anchor regions and stabilize predicted mmu-let-7a:mRNA duplexes

Jeffrey Reid — 2008-07-14T07:04:36-00:00

Genome Res. (9 July 2008), gr.078246.108.

Massively parallel sequencing of millions of <30 nt RNAs expressed in mouse ovary, embryonic pancreas (E14.5) and insulin-secreting beta-cells (TC-3) reveals that ~50% of the mature miRNAs representing mostly the mmu-let-7 family display internal insertion/deletions and substitutions when compared to precursor miRNA and the mouse genome reference sequences. Approximately, 12-20% of species associated with mmu-let-7 populations exhibits sequence discrepancies that are dramatically reduced in nucleotides 3-7 (5'-seed) and 10-15 (cleavage and anchor sites). This observation is inconsistent with sequencing error and leads us to propose that the changes arise predominantly from post-transcriptional RNA editing activity operating on miRNA:target mRNA complexes. Internal nucleotide modifications are most enriched at the 9th nucleotide position. A common 9th base edit of U-to-G results in a significant increase in stability of down regulated let-7a targets in inhibin knockout mutants (Inha-/-). An excess of U-insertions (14.8%) over U-deletions (1.5%) and the presence of cleaved intermediates suggests that a mammalian TUTase (terminal uridylyl transferase) mediated dUTP-dependent U-insertion/U-deletion cycle maybe a possible mechanism. We speculate that mRNA target site-directed editing of mmu-let-7a duplex-bulges stabilizes 'loose' miRNA:mRNA target associations and functions to expand the target repertoire and/or enhance mRNA decay over translational repression. Our results also demonstrate that the systematic study of sequence variation within specific RNA classes in a given cell type from millions of sequences generated by next generation sequencing (NGS) technologies ('intranomics') can be used broadly to infer functional constraints on specific parts of completely uncharacterized RNAs. 10.1101/gr.078246.108

MicroRNA regulation and the variability of human cortical gene expression.

Rui Zhang — 2008-07-14T07:01:14-00:00

Nucleic acids research (10 July 2008)

Understanding the driving forces of gene expression variation within human populations will provide important insights into the molecular basis of human phenotypic variation. In the genome, the gene expression variability differs among genes, and at present, most research has focused on identifying the genetic variants responsible for the within population gene expression variation. However, little is known about whether microRNAs (miRNAs), which are small noncoding RNAs modulating expression of their target genes, could have impact on the variability of gene expression. Here we demonstrate that miRNAs likely lead to the difference of expression variability among genes. With the use of the genome-wide expression data in 193 human brain samples, we show that the increased variability of gene expression is concomitant with the increased number of the miRNA seeds interacting with the target genes, suggesting a direct influence of miRNA on gene expression variability. Compared with the non-miRNA-target genes, genes targeted by more than two miRNA seeds have increased expression variability, independent of the miRNA types. In addition, single-nucleotide polymorphisms (SNPs) located in the miRNA binding sites could further increase the gene expression variability of the target genes. We propose that miRNAs are one of the driving forces causing expression variability in the human genome.

Coherent Coupling of Feedback Loops: A Design Principle of Cell Signaling Networks.

Yung-Keun Kwon — 2008-07-06T06:28:52-00:00

Bioinformatics (Oxford, England) (2 July 2008)

MOTIVATION: It is widely accepted that cell signaling networks have been evolved to be robust against perturbations. To investigate the topological characteristics resulting in such robustness, we have examined large-scale signaling networks and found that a number of feedback loops are present mostly in coupled structures. In particular, the coupling was made in a coherent way implying that same types of feedback loops are interlinked together. RESULTS: We have investigated the role of such coherently coupled feedback loops through extensive Boolean network simulations and found that a high proportion of coherent couplings can enhance the robustness of a network against its state perturbations. Moreover, we found that the robustness achieved by coherently coupled feedback loops can be kept evolutionarily stable. All these results imply that the coherent coupling of feedback loops might be a design principle of cell signaling networks devised to achieve the robustness. CONTACT: ckh@kaist.ac.kr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Identifying gene-disease associations using centrality on a literature mined gene-interaction network

Arzucan Ozgur — 2008-07-02T08:06:17-00:00

Bioinformatics, Vol. 24, No. 13. (1 July 2008), pp. i277-285.

Motivation: Understanding the role of genetics in diseases is one of the most important aims of the biological sciences. The completion of the Human Genome Project has led to a rapid increase in the number of publications in this area. However, the coverage of curated databases that provide information manually extracted from the literature is limited. Another challenge is that determining disease-related genes requires laborious experiments. Therefore, predicting good candidate genes before experimental analysis will save time and effort. We introduce an automatic approach based on text mining and network analysis to predict gene-disease associations. We collected an initial set of known disease-related genes and built an interaction network by automatic literature mining based on dependency parsing and support vector machines. Our hypothesis is that the central genes in this disease-specific network are likely to be related to the disease. We used the degree, eigenvector, betweenness and closeness centrality metrics to rank the genes in the network. Results: The proposed approach can be used to extract known and to infer unknown gene-disease associations. We evaluated the approach for prostate cancer. Eigenvector and degree centrality achieved high accuracy. A total of 95% of the top 20 genes ranked by these methods are confirmed to be related to prostate cancer. On the other hand, betweenness and closeness centrality predicted more genes whose relation to the disease is currently unknown and are candidates for experimental study. Availability: A web-based system for browsing the disease-specific gene-interaction networks is available at: http://gin.ncibi.org Contact: radev@umich.edu 10.1093/bioinformatics/btn182

The mechanism of micro-RNA-mediated translation repression is determined by the promoter of the target gene

Yi Kong — 2008-06-28T12:39:37-00:00

Proceedings of the National Academy of Sciences (25 June 2008), 0800650105.

MicroRNAs (miRNAs) are noncoding RNAs that base pair imperfectly to homologous regions in target mRNAs and negatively influence the synthesis of the corresponding proteins. Repression is mediated by a number of mechanisms, one of which is the direct inhibition of protein synthesis. Surprisingly, previous studies have suggested that two mutually exclusive mechanisms exist, one acting at the initiation phase of protein synthesis and the other at a postinitiation event. Here, we resolve this apparent dichotomy by demonstrating that the promoter used to transcribe the mRNA influences the type of miRNA-mediated translational repression. Transcripts derived from the SV40 promoter that contain let-7 target sites in their 3' UTRs are repressed at the initiation stage of translation, whereas essentially identical mRNAs derived from the TK promoter are repressed at a postinitiation step. We also show that there is a miR-34 target site within the 3' UTR of c-myc mRNA and that promoter dependency is also true for this endogenous 3' UTR. Overall, these data establish a link between the nuclear history of an mRNA and the mechanism of miRNA-mediated translational regulation in the cytoplasm. 10.1073/pnas.0800650105

BioGraphE: high-performance bionetwork analysis using the Biological Graph Environment

George Chin — 2008-06-28T12:39:39-00:00

BMC Bioinformatics, Vol. 9, No. Suppl 6. (2008)

BACKGROUND:Graphs and networks are common analysis representations for biological systems. Many traditional graph algorithms such as k-clique, k-coloring, and subgraph matching have great potential as analysis techniques for newly available data in biology. Yet, as the amount of genomic and bionetwork information rapidly grows, scientists need advanced new computational strategies and tools for dealing with the complexities of the bionetwork analysis and the volume of the data.RESULTS:We introduce a computational framework for graph analysis called the Biological Graph Environment (BioGraphE), which provides a general, scalable integration platform for connecting graph problems in biology to optimized computational solvers and high-performance systems. This framework enables biology researchers and computational scientists to identify and deploy network analysis applications and to easily connect them to efficient and powerful computational software and hardware that are specifically designed and tuned to solve complex graph problems. In our particular application of BioGraphE to support network analysis in genome biology, we investigate the use of a Boolean satisfiability solver known as Survey Propagation as a core computational solver executing on standard high-performance parallel systems, as well as multi-threaded architectures.CONCLUSION:In our application of BioGraphE to conduct bionetwork analysis of homology networks, we found that BioGraphE and a custom, parallel implementation of the Survey Propagation SAT solver were capable of solving very large bionetwork problems at high rates of execution on different high-performance computing platforms.

An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP.

Gary A Wayman — 2008-06-27T07:27:12-00:00

Proceedings of the National Academy of Sciences of the United States of America (24 June 2008)

Activity-regulated gene expression is believed to play a key role in the development and refinement of neuronal circuitry. Nevertheless, the transcriptional networks that regulate synapse growth and plasticity remain largely uncharacterized. Here, we show that microRNA 132 (miR132) is an activity-dependent rapid response gene regulated by the cAMP response element-binding (CREB) protein pathway. Introduction of miR132 into hippocampal neurons enhanced dendrite morphogenesis whereas inhibition of miR132 by 2'O-methyl RNA antagonists blocked these effects. Furthermore, neuronal activity inhibited translation of p250GAP, a miR132 target, and siRNA-mediated knockdown of p250GAP mimicked miR132-induced dendrite growth. Experiments using dominant-interfering mutants suggested that Rac signaling is downstream of miR132 and p250GAP. We propose that the miR132-p250GAP pathway plays a key role in activity-dependent structural and functional plasticity.

MicroRNA Expression and Identification of Putative miRNA Targets in Ovarian Cancer

Neetu Dahiya — 2008-06-19T07:06:19-00:00

PLoS ONE, Vol. 3, No. 6. (18 June 2008), e2436.

Background: MicroRNAs (miRNAs) represent a class of small non-coding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Emerging evidence suggests the potential involvement of altered regulation of miRNA in the pathogenesis of cancers, and these genes are thought to function as both tumor suppressors and oncogenes. Methodology/Principal Findings: Using microRNA microarrays, we identify several miRNAs aberrantly expressed in human ovarian cancer tissues and cell lines. miR-221 stands out as a highly elevated miRNA in ovarian cancer, while miR-21 and several members of the let-7 family are found downregulated. Public databases were used to reveal potential targets for the highly differentially expressed miRNAs. In order to experimentally identify transcripts whose stability may be affected by the differentially expressed miRNAs, we transfected precursor miRNAs into human cancer cell lines and used oligonucleotide microarrays to examine changes in the mRNA levels. Interestingly, there was little overlap between the predicted and the experimental targets or pathways, or between experimental targets/pathways obtained using different cell lines, highlighting the complexity of miRNA target selection. Conclusion/Significance: Our results identify several differentially expressed miRNAs in ovarian cancer and identify potential target transcripts that may be regulated by these miRNAs. These miRNAs and their targets may have important roles in the initiation and development of ovarian cancer.

Inducible expression of microRNA-194 is regulated by HNF-1alpha during intestinal epithelial cell differentiation.

Kimihiro Hino — 2008-05-23T08:03:22-00:00

RNA (New York, N.Y.) (20 May 2008)

Maintenance of the intestinal epithelium is based on well-balanced molecular mechanisms that confer the stable and continuous supply of specialized epithelial cell lineages from multipotent progenitors. Lineage commitment decisions in the intestinal epithelium system involve multiple regulatory systems that interplay with each other to establish the cellular identities. Here, we demonstrate that the microRNA system could be involved in intestinal epithelial cell differentiation, and that microRNA-194 (miR-194) is highly induced during this process. To investigate this inducible expression mechanism, we identified the genomic structure of the miR-194-2, -192 gene, one of the inducible class of miR-194 parental genes. Furthermore, we identified its transcriptional regulatory region that contains a consensus-binding motif for hepatocyte nuclear factor-1alpha (HNF-1alpha), which is well known as a transcription factor to regulate gene expression in intestinal epithelial cells. By chromatin immunoprecipitation assay and luciferase reporter analysis, we revealed that pri-miR-194-2 expression is controlled by HNF-1alpha, and its consensus binding region is required for the transcription of pri-miR-194-2 in vivo in an intestinal epithelial cell line, Caco-2. Our observations indicate that microRNA genes could be targets of lineage-specific transcription factors and that microRNAs are regulated by a tissue-specific manner in the intestinal epithelium. Therefore, our work suggests that induced expression of these microRNAs have important roles in intestinal epithelium maturation.

A novel noncoding RNA processed by Drosha is restricted to nucleus in mouse

Gayatri Ganesan — 2008-06-19T07:02:59-00:00

RNA, Vol. 14, No. 7. (1 July 2008), pp. 1399-1410.

Noncoding RNAs constitute a huge repertoire of gene regulatory molecules. Our previous, fine-resolution characterization of a mouse meiotic recombination hotspot from chromosome 8 resulted in identification of 2.4-kb unspliced and polyadenylated noncoding mrhl RNA. The gene is expressed in multiple tissues and is also present in rat but absent in humans. Here we report that the mrhl RNA gets processed to a small 80-nucleotide (nt) RNA species and is mediated by the Drosha complex. We also observe that the 80-nt Drosha product could be processed further to a 22-nt small RNA by Dicer in an in vitro reaction. However, this 22-nt product was not detected in vivo. The 80-nt as well as the 2.4-kb full-length RNA are nuclear-localized, showing distinct punctate nuclear signal. The colocalization of the noncoding RNA with Drosha and Nucleolin suggests the nucleolus as the site of processing of the 2.4-kb primary transcript. Additional foci of the processed 80-nt RNA were also observed outside the nucleolus, suggesting its role in some specific chromatin domain(s). Thus, this study reports a novel noncoding mrhl RNA that is processed and restricted within the cell nucleus. 10.1261/rna.838308

The 3'-UTR mediates the cellular localization of an mRNA encoding a short plasma membrane protein

Adi Loya — 2008-06-19T07:02:33-00:00

RNA, Vol. 14, No. 7. (1 July 2008), pp. 1352-1365.

Cotranslational synthesis of proteins into the endoplasmic reticulum is preceded by targeting of the translating mRNA once a signal peptide emerges from the ribosome exit tunnel. Many mRNAs, however, are unlikely to be targeted by this process because they encode proteins that do not contain a signal peptide or because they are too short to be recognized by the signal recognition particle. Herein we tested the possible involvement of the 3'-UTR in the localization of an mRNA that encodes a very short Saccharomyces cerevisiae protein (Pmp1). We found by ribosome density mapping, sedimentation analysis, differential centrifugation, and fluorescent in situ hybridization that the 3'-UTR is essential for the association of the transcript with membrane compartments. Fusion of the 3'-UTR to heterologous open reading frames conferred on them a sedimentation and cellular localization pattern resembling that of PMP1. Mutation analysis revealed that a repeating UG-rich sequence within the 3'-UTR is important for membrane association. Taken together, our results reveal an essential role for elements within the 3'-UTR in the localization of an mRNA that is likely to be ignored by the standard signal-dependant mechanism. 10.1261/rna.867208

Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks.

Jun Zhu — 2008-06-18T06:58:33-00:00

Nature genetics (15 June 2008)

A key goal of biology is to construct networks that predict complex system behavior. We combine multiple types of molecular data, including genotypic, expression, transcription factor binding site (TFBS), and protein-protein interaction (PPI) data previously generated from a number of yeast experiments, in order to reconstruct causal gene networks. Networks based on different types of data are compared using metrics devised to assess the predictive power of a network. We show that a network reconstructed by integrating genotypic, TFBS and PPI data is the most predictive. This network is used to predict causal regulators responsible for hot spots of gene expression activity in a segregating yeast population. We also show that the network can elucidate the mechanisms by which causal regulators give rise to larger-scale changes in gene expression activity. We then prospectively validate predictions, providing direct experimental evidence that predictive networks can be constructed by integrating multiple, appropriate data types.

Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells

Morgan Carlson — 2008-06-16T16:44:28-00:00

Nature (15 June 2008)

Discovering functional interaction patterns in protein-protein interaction networks

Mehmet Turanalp — 2008-06-12T05:37:02-00:00

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

BACKGROUND:In recent years, a considerable amount of research effort has been directed to the analysis of biological networks with the availability of genome-scale networks of genes and/or proteins of an increasing number of organisms. A protein-protein interaction (PPI) network is a particular biological network which represents physical interactions between pairs of proteins of an organism. Major research on PPI networks has focused on understanding the topological organization of PPI networks, evolution of PPI networks and identification of conserved subnetworks across different species, discovery of modules of interaction, use of PPI networks for functional annotation of uncharacterized proteins, and improvement of the accuracy of currently available networks.RESULTS:In this article, we map known functional annotations of proteins onto a PPI network in order to identify frequently occurring interaction patterns in the functional space. We propose a new frequent pattern identification technique, PPISpan, adapted specifically for PPI networks from a well-known frequent subgraph identification method, gSpan. Existing module discovery techniques either look for specific clique-like highly interacting protein clusters or linear paths of interaction. However, our goal is different; instead of single clusters or pathways, we look for recurring functional interaction patterns in arbitrary topologies. We have applied PPISpan on PPI networks of Saccharomyces cerevisiae and identified a number of frequently occurring functional interaction patterns.CONCLUSIONS:With the help of PPISpan, recurring functional interaction patterns in an organism's PPI network can be identified. Such an analysis offers a new perspective on the modular organization of PPI networks. The complete list of identified functional interaction patterns is available at http://bioserver.ceng.metu.edu.tr/PPISpan/.

SMAD proteins control DROSHA-mediated microRNA maturation

Brandi Davis — 2008-06-12T04:36:14-00:00

Nature (11 June 2008)

Comparative Pathway Analyzer--a web server for comparative analysis, clustering and visualization of metabolic networks in multiple organisms.

Sebastian Oehm — 2008-06-11T07:13:22-00:00

Nucleic acids research (6 June 2008)

In order to understand the phenotype of any living system, it is essential to not only investigate its genes, but also the specific metabolic pathway variant of the organism of interest, ideally in comparison with other organisms. The Comparative Pathway Analyzer, CPA, calculates and displays the differences in metabolic reaction content between two sets of organisms. Because results are highly dependent on the distribution of organisms into these two sets and the appropriate definition of these sets often is not easy, we provide hierarchical clustering methods for the identification of significant groupings. CPA also visualizes the reaction content of several organisms simultaneously allowing easy comparison. Reaction annotation data and maps for visualizing the results are taken from the KEGG database. Additionally, users can upload their own annotation data. This website is free and open to all users and there is no login requirement. It is available at https://www.cebitec.uni-bielefeld.de/groups/brf/software/cpa/index.html.

Downregulation of MIRNA-1/MIRNA-133 contributes to re-expression of pacemaker channel genes HCN2 and HCN4 in hypertrophic heart.

Xiaobin Luo — 2008-05-14T20:36:21-00:00

The Journal of biological chemistry (5 May 2008)

Cardiac hypertrophy is characterized by electrical remolding with increased risk of arrhythmogenesis. Enhanced abnormal automaticity of ventricular cells contributes critically to hypertrophic arrhythmias. The pacemaker current If, carried by the hyperpolarization-activated channels encoded mainly by the HCN2 and HCN4 genes in the heart, plays an important role in determining cardiac automaticity. Their expressions reportedly increase in hypertrophic and failing hearts, contributing to arrhythmogenesis under these conditions. We performed a study on post-transcriptional regulation of expression of HCN2 and HCN4 genes by microRNAs. We experimentally established HCN2 as a target for repression by the muscle-specific microRNAs miR-1 and miR-133, and HCN4 as a target for miR-1 only. We unraveled robust increases in HCN2 and HCN4 protein levels in a rat model of left ventricular hypertrophy and in angiotensin II-induced neonatal ventricular hypertrophy. The upregulation of HCN2/HCN4 was accompanied by pronounced reduction of miR-1/miR-133 levels. Forced expression of miR-1/miR-133 by transfection prevented overexpression of HCN2/HCN4 in hypertrophic cardiomyocytes. The serum responsive factor (SRF) protein level was found significantly decreased in hypertrophic hearts and silencing of SRF by RNAi resulted in increased levels of miR-1/miR-133 and concomitant increases in HCN2 and HCN4 protein levels. We conclude that down-regulation of miR-1 and miR-133 expression contributes to re-expression of HCN2/HCN4 thereby the electrical remodeling process in hypertrophic hearts. Our study also sheds new light on the cellular function and pathological role of miR-1/miR-133 in the heart.

MicroRNA regulation and interspecific variation of gene expression.

Qinghua Cui — 2007-05-08T13:41:17-00:00

Trends Genet (3 May 2007)

MicroRNAs (miRNAs) modulate expression of their target genes in various tissues and at different developmental stages, but it is unclear whether they drive cross-species variation in gene expression. By comparing data from mammal and fly species we found that the cross-species expression variation of miRNA targets is significantly lower than that of other genes. This implies that miRNAs can affect gene expression by reducing stochastic noise, buffering cross-species variation and constraining evolutionary gene expression variation.

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.

MicroRNA-21 Targets Sprouty2 and Promotes Cellular Outgrowths.

Danish Sayed — 2008-06-02T09:08:14-00:00

Molecular biology of the cell (28 May 2008)

Monitoring Editor: Jonathan Chernoff The post-transcriptional regulator, microRNA-21 (miR-21), is up-regulated in many forms of cancer, as well as, during cardiac hypertrophic growth. To understand its role, we overexpressed it in cardiocytes where it revealed a unique type of cell-to-cell 'linker' in the form of long slender outgrowths/branches. We subsequently confirmed that miR-21 directly targets and down-regulates the expression of sprouty2 (SPRY2), an inhibitor of branching morphogenesis and neurite outgrowths. We found that beta-adrenergic receptor (betaAR) stimulation induces upregulation of miR-21 and down-regulation of SPRY2 and is, likewise, associated with connecting cell branches. Knockdown of SPRY2 reproduced the branching morphology in cardiocytes, and vice versa, knockdown of miR-21 using a specific 'miRNA eraser' or overexpression of SPRY2 inhibited betaAR-induced cellular outgrowths. These structures enclose sarcomeres and connect adjacent cardiocytes through functional gap junctions. To determine how this aspect of miR-21 function translates in cancer cells, we knocked it down in colon cancer SW480 cells. This resulted in disappearance of their microvillus-like protrusions accompanied by SPRY2-dependent inhibition of cell migration. Thus, we propose that an increase in miR-21 enhances the formation of various types of cellular protrusions through directly targeting and down-regulating SPRY2.

A MicroRNA Feedback Circuit in Midbrain Dopamine Neurons.

J Kim — 2007-09-01T16:00:44-00:00

Science, Vol. 317, No. 5842. (31 August 2007), pp. 1220-1224.

MicroRNAs (miRNAs) are evolutionarily conserved, 18- to 25-nucleotide, non-protein coding transcripts that posttranscriptionally regulate gene expression during development. miRNAs also occur in postmitotic cells, such as neurons in the mammalian central nervous system, but their function is less well characterized. We investigated the role of miRNAs in mammalian midbrain dopaminergic neurons (DNs). We identified a miRNA, miR-133b, that is specifically expressed in midbrain DNs and is deficient in midbrain tissue from patients with Parkinson's disease. miR-133b regulates the maturation and function of midbrain DNs within a negative feedback circuit that includes the paired-like homeodomain transcription factor Pitx3. We propose a role for this feedback circuit in the fine-tuning of dopaminergic behaviors such as locomotion.

The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes

Chaoqian Xu — 2008-05-28T13:40:52-00:00

J Cell Sci, Vol. 120, No. 17. (1 September 2007), pp. 3045-3052.

The microRNAs miR-1 and miR-133 are preferentially expressed in cardiac and skeletal muscles and have been shown to regulate differentiation and proliferation of these cells. We report here a novel aspect of cellular function of miR-1 and miR-133 regulation of cardiomyocyte apoptosis. miR-1 and miR-133 produced opposing effects on apoptosis, induced by oxidative stress in H9c2 rat ventricular cells, with miR-1 being pro-apoptotic and miR-133 being anti-apoptotic. miR-1 level was significantly increased in response to oxidative stress. We identified single target sites for miR-1 only, in the 3'-untranslated regions of the HSP60 and HSP70 genes, and multiple putative target sites for miR-133 throughout the sequence of the caspase-9 gene. miR-1 reduced the levels of HSP60 and HSP70 proteins without changing their transcript levels, whereas miR-133 did not affect HSP60 and HSP70 expression at all. By contrast, miR-133 repressed caspase-9 expression at both the protein and mRNA levels. The post-transcriptional repression of HSP60 and HSP70 and caspase-9 was further confirmed by luciferase reporter experiments. Our results indicate that miR-1 and miR-133 are involved in regulating cell fate with increased miR-1 and/or decreased miR-133 levels favoring apoptosis and decreased miR-1 and/or miR-133 levels favoring survival. Post-transcriptional repression of HSP60 and HSP70 by miR-1 and of caspase-9 by miR-133 contributes significantly to their opposing actions. 10.1242/jcs.010728

Taking microRNAs to heart.

Thomas E Callis — 2008-05-28T12:34:46-00:00

Trends in molecular medicine (3 May 2008)

MicroRNAs (miRNAs) are a class of highly conserved, small non-coding RNAs that regulate gene expression post-transcriptionally. The emerging field of miRNA biology has begun to reveal roles for these regulatory molecules in a wide range of biological processes. Dysregulated miRNA expression has been correlated to diseased hearts in human patients, whereas inhibiting the maturation of miRNAs conditionally in murine hearts has revealed that miRNAs are essential for cardiac development and function. Moreover, genetic studies have identified distinct roles for specific miRNAs during cardiogenesis, cardiac hypertrophy and electrical conduction. These previously unrecognized relationships shed new light on the regulatory mechanisms underlying heart development and pathology and suggest the potential importance of miRNAs as diagnostic markers and therapeutic targets for cardiovascular disease.

MicroRNA promoter element discovery in Arabidopsis.

Molly Megraw — 2006-08-22T17:26:16-00:00

RNA (3 August 2006)

In this study we present a method of identifying Arabidopsis miRNA promoter elements using known transcription factor binding motifs. We provide a comparative analysis of the representation of these elements in miRNA promoters, protein-coding gene promoters, and random genomic sequences. We report five transcription factor (TF) binding motifs that show evidence of overrepresentation in miRNA promoter regions relative to the promoter regions of protein-coding genes. This investigation is based on the analysis of 800-nucleotide regions upstream of 63 experimentally verified Transcription Start Sites (TSS) for miRNA primary transcripts in Arabidopsis. While the TATA-box binding motif was also previously reported by Xie and colleagues, the transcription factors AtMYC2, ARF, SORLREP3, and LFY are identified for the first time as overrepresented binding motifs in miRNA promoters.

A GATA-1-regulated microRNA locus essential for erythropoiesis

Louis Dore — 2008-05-08T11:31:30-00:00

Proceedings of the National Academy of Sciences, Vol. 105, No. 9. (4 March 2008), pp. 3333-3338.

MicroRNAs (miRNAs) control tissue development, but their mechanism of regulation is not well understood. We used a gene complementation strategy combined with microarray screening to identify miRNAs involved in the formation of erythroid (red blood) cells. Two conserved miRNAs, miR 144 and miR 451, emerged as direct targets of the critical hematopoietic transcription factor GATA-1. In vivo, GATA-1 binds a distal upstream regulatory element to activate RNA polymerase II-mediated transcription of a single common precursor RNA (pri-miRNA) encoding both mature miRNAs. Zebrafish embryos depleted of miR 451 by using antisense morpholinos form erythroid precursors, but their development into mature circulating red blood cells is strongly and specifically impaired. These results reveal a miRNA locus that is required for erythropoiesis and uncover a new regulatory axis through which GATA-1 controls this process. 10.1073/pnas.0712312105

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.

Fgf8 expression defines a morphogenetic center required for olfactory neurogenesis and nasal cavity development in the mouse

Shimako Kawauchi — 2008-05-19T11:43:56-00:00

Development, Vol. 132, No. 23. (1 December 2005), pp. 5211-5223.

In vertebrate olfactory epithelium (OE), neurogenesis proceeds continuously, suggesting that endogenous signals support survival and proliferation of stem and progenitor cells. We used a genetic approach to test the hypothesis that Fgf8 plays such a role in developing OE. In young embryos, Fgf8 RNA is expressed in the rim of the invaginating nasal pit (NP), in a small domain of cells that overlaps partially with that of putative OE neural stem cells later in gestation. In mutant mice in which the Fgf8 gene is inactivated in anterior neural structures, FGF-mediated signaling is strongly downregulated in both OE proper and underlying mesenchyme by day 10 of gestation. Mutants survive gestation but die at birth, lacking OE, vomeronasal organ (VNO), nasal cavity, forebrain, lower jaw, eyelids and pinnae. Analysis of mutants indicates that although initial NP formation is grossly normal, cells in the Fgf8-expressing domain undergo high levels of apoptosis, resulting in cessation of nasal cavity invagination and loss of virtually all OE neuronal cell types. These findings demonstrate that Fgf8 is crucial for proper development of the OE, nasal cavity and VNO, as well as maintenance of OE neurogenesis during prenatal development. The data suggest a model in which Fgf8 expression defines an anterior morphogenetic center, which is required not only for the sustenance and continued production of primary olfactory (OE and VNO) neural stem and progenitor cells, but also for proper morphogenesis of the entire nasal cavity. 10.1242/dev.02143

The time of appearance of the C. elegans let-7 microRNA is transcriptionally controlled utilizing a temporal regulatory element in its promoter.

SM Johnson — 2005-11-21T15:51:54-00:00

Dev Biol, Vol. 259, No. 2. (15 July 2003), pp. 364-379.

MicroRNAs (miRNAs) are a large family of small regulatory RNAs that are poorly understood. The let-7 miRNA regulates the timing of the developmental switch from larval to adult cell fates during Caenorhabditis elegans development. Expression of let-7 RNA is temporally regulated, with robust expression in the fourth larval and adult stages. Here, we show that, like let-7 RNA, a transcriptional fusion of the let-7 promoter to gfp is temporally regulated, indicating that let-7 is transcriptionally controlled. Temporal upregulation of let-7 transcription requires an enhancer element, the temporal regulatory element (TRE), situated about 1200 base pairs upstream of the start of the mature let-7 RNA. The TRE is both necessary and sufficient for this temporal upregulation. A TRE binding factor (TREB) is able to bind to the TRE, and a 22-base pair inverted repeat within the TRE is necessary and sufficient for this binding. We also find that the nuclear hormone receptor DAF-12 and the RNA binding protein LIN-28 are both required for the correct timing of let-7 RNA and let-7::gfp expression. We speculate that these heterochronic genes regulate let-7 expression through its TRE.

Denoising feedback loops by thresholding--a new role for microRNAs.

SM Cohen — 2006-10-18T16:35:39-00:00

Genes Dev, Vol. 20, No. 20. (15 October 2006), pp. 2769-2772.

Direct regulation of an oncogenic microRNA cluster by E2F transcription factors.

Keith Woods — 2006-12-05T00:28:05-00:00

J Biol Chem (29 November 2006)

MicroRNAs (miRNAs) are a class of non-coding RNAs that post-transcriptionally regulate gene expression via the RNA interference (RNAi) pathway. In addition to roles in normal development, miRNAs have recently been implicated in a range of human diseases, including cancer. We recently demonstrated that a polycistronic cluster of miRNAs, miR-17~92, is oncogenic in a mouse model for Burkitt's lymphoma. This is due, in part, to a reduced apoptotic program. In an effort to understand the regulation of miR-17~92, we have studied the promoter structure of this miRNA cluster. The primary transcript initiates from a consensus initiator sequence downstream of a nonconsensus TATA box. The core promoter region contains two functional E2F transcription factor binding sites. Chromatin immunoprecipitation demonstrates that E2F3 is the primary E2F family member that occupies the promoter. These data place miR-17~92 in a regulatory loop between E2F3 and the miR-17 target E2F1. We propose a model whereby miR-17~92 promotes cell proliferation by shifting the E2F transcriptional balance away from the pro-apoptotic E2F1 and towards the proliferative E2F3 transcriptional network.

A functional study of miR-124 in the developing neural tube.

X Cao — 2007-03-22T16:56:44-00:00

Genes Dev, Vol. 21, No. 5. (1 March 2007), pp. 531-536.

Neural development is a highly orchestrated process that entails precise control of gene expression. Although microRNAs (miRNAs) have been implicated in fine-tuning gene networks, the roles of individual miRNAs in vertebrate neural development have not been studied in vivo. We investigated the function of the most abundant neuronal miRNA, miR-124, during spinal cord development. Neither inhibition nor overexpression of miR-124 significantly altered the acquisition of neuronal fate, suggesting that miR-124 is unlikely to act as a primary determinant of neuronal differentiation. Two endogenous targets of miR-124, laminin gamma 1 and integrin beta1, were identified, both of which are highly expressed by neural progenitors but repressed upon neuronal differentiation. Thus miR-124 appears to ensure that progenitor genes are post-transcriptionally inhibited in neurons.

MicroRNA-155 is induced during the macrophage inflammatory response.

RM O'connell — 2007-02-07T16:28:17-00:00

Proc Natl Acad Sci U S A, Vol. 104, No. 5. (30 January 2007), pp. 1604-1609.

The mammalian inflammatory response to infection involves the induction of several hundred genes, a process that must be carefully regulated to achieve pathogen clearance and prevent the consequences of unregulated expression, such as cancer. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators that has also been linked to cancer. However, the relationship between inflammation, innate immunity, and miRNA expression is just beginning to be explored. In the present study, we use microarray technology to identify miRNAs induced in primary murine macrophages after exposure to polyriboinosinic:polyribocytidylic acid or the cytokine IFN-beta. miR-155 was the only miRNA of those tested that was substantially up-regulated by both stimuli. It also was induced by several Toll-like receptor ligands through myeloid differentiation factor 88- or TRIF-dependent pathways, whereas up-regulation by IFNs was shown to involve TNF-alpha autocrine signaling. Pharmacological inhibition of the kinase JNK blocked induction of miR-155 in response to either polyriboinosinic:polyribocytidylic acid or TNF-alpha, suggesting that miR-155-inducing signals use the JNK pathway. Together, these findings characterize miR-155 as a common target of a broad range of inflammatory mediators. Importantly, because miR-155 is known to function as an oncogene, these observations identify a potential link between inflammation and cancer.

NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses.

KD Taganov — 2007-02-21T23:21:15-00:00

Proc Natl Acad Sci U S A, Vol. 103, No. 33. (15 August 2006), pp. 12481-12486.

Activation of mammalian innate and acquired immune responses must be tightly regulated by elaborate mechanisms to control their onset and termination. MicroRNAs have been implicated as negative regulators controlling diverse biological processes at the level of posttranscriptional repression. Expression profiling of 200 microRNAs in human monocytes revealed that several of them (miR-146a/b, miR-132, and miR-155) are endotoxin-responsive genes. Analysis of miR-146a and miR-146b gene expression unveiled a pattern of induction in response to a variety of microbial components and proinflammatory cytokines. By means of promoter analysis, miR-146a was found to be a NF-kappaB-dependent gene. Importantly, miR-146a/b were predicted to base-pair with sequences in the 3' UTRs of the TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 genes, and we found that these UTRs inhibit expression of a linked reporter gene. These genes encode two key adapter molecules downstream of Toll-like and cytokine receptors. Thus, we propose a role for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor-associated factor 6 protein levels.

Tumour invasion and metastasis initiated by microRNA-10b in breast cancer

Li Ma — 2007-10-02T16:57:02-00:00

Nature (26 September 2007)

Putative promoter regions of miRNA genes involved in evolutionarily conserved regulatory systems among vertebrates.

Shuji Fujita — 2007-12-10T08:17:28-00:00

Bioinformatics (30 November 2007)

MOTIVATION: Just as transcription factors, miRNA genes modulate global patterns of gene expression during differentiation, metabolic activation, stimulus response and also carcinogenesis. However, little is currently known how the miRNA gene expression itself is regulated owing to lack of basic information of their gene structure. Global prediction of promoter regions of miRNA genes would allow us to explore the mechanisms underlying gene-regulatory mechanisms involving these miRNAs. RESULTS: We speculate that if specific miRNA molecules are involved in evolutionarily conserved regulatory systems in vertebrates, this would entail a high level of conservation of the promoter of miRNA gene as well as the miRNA molecule. By our current screening of putative promoter regions of miRNA genes (miPPRs) on this base, we identified 59 miPPRs that would direct production of 79 miRNAs. We present both biochemical and bioinformatical verifications of these putative promoters.

MicroRNAs and Immunity: Tiny Players in a Big Field.

KD Taganov — 2008-05-15T11:28:29-00:00

Immunity, Vol. 26 (23 February 2007), pp. 133-137.

Regulation of the germinal center response by microRNA-155.

TH Thai — 2007-04-28T15:16:25-00:00

Science, Vol. 316, No. 5824. (27 April 2007), pp. 604-608.

MicroRNAs are small RNA species involved in biological control at multiple levels. Using genetic deletion and transgenic approaches, we show that the evolutionarily conserved microRNA-155 (miR-155) has an important role in the mammalian immune system, specifically in regulating T helper cell differentiation and the germinal center reaction to produce an optimal T cell-dependent antibody response. miR-155 exerts this control, at least in part, by regulating cytokine production. These results also suggest that individual microRNAs can exert critical control over mammalian differentiation processes in vivo.

Regulation of pri-microRNA BIC transcription and processing in Burkitt lymphoma

J Kluiver — 2006-12-18T09:20:40-00:00

Oncogene, Vol. aop, No. current.

Systematic Identification of mRNAs Recruited to Argonaute 2 by Specific microRNAs and Corresponding Changes in Transcript Abundance.

DG Hendrickson — 2008-05-08T19:09:14-00:00

PLoS ONE, Vol. 3, No. 5. (2008)

microRNAs (miRNAs) are small non-coding RNAs that regulate mRNA stability and translation through the action of the RNAi-induced silencing complex (RISC). Our current understanding of miRNA function is inferred largely from studies of the effects of miRNAs on steady-state mRNA levels and from seed match conservation and context in putative targets. Here we have taken a more direct approach to these issues by comprehensively assessing the miRNAs and mRNAs that are physically associated with Argonaute 2 (Ago2), which is a core RISC component. We transfected HEK293T cells with epitope-tagged Ago2, immunopurified Ago2 together with any associated miRNAs and mRNAs, and quantitatively determined the levels of these RNAs by microarray analyses. We found that Ago2 immunopurified samples contained a representative repertoire of the cell's miRNAs and a select subset of the cell's total mRNAs. Transfection of the miRNAs miR-1 and miR-124 caused significant changes in the association of scores of mRNAs with Ago2. The mRNAs whose association with Ago2 increased upon miRNA expression were much more likely to contain specific miRNA seed matches and to have their overall mRNA levels decrease in response to the miRNA transfection than expected by chance. Hundreds of mRNAs were recruited to Ago2 by each miRNA via seed sequences in 3'-untranslated regions and coding sequences and a few mRNAs appear to be targeted via seed sequences in 5'-untranslated regions. Microarray analysis of Ago2 immunopurified samples provides a simple, direct method for experimentally identifying the targets of miRNAs and for elucidating roles of miRNAs in cellular regulation.

B-cell receptor activation induces BIC/miR-155 expression through a conserved AP-1 element.

Q Yin — 2008-04-29T14:49:28-00:00

The Journal of biological chemistry, Vol. 283, No. 5. (1 February 2008), pp. 2654-2662.

microRNA-155 is an oncogenic microRNA that has been shown to be critical for B-cell maturation and immunoglobulin production in response to antigen. In line with its function in B-cell activation, miR-155, and its primary transcript, B-cell integration cluster (BIC), is induced by B-cell receptor (BCR) cross-linking. Using pharmacological inhibitors in the human B-cell line, Ramos, we show that activation of BIC and miR-155 expression by BCR signaling occurs through the extracellular signaling-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways but not the p38 pathway. BCR activation results in the induction of c-Fos, FosB, and JunB, and expression of these are suppressed by ERK and JNK inhibitors. Reporter analysis established a key role for a conserved AP-1 site approximately 40 bp upstream from the site of initiation but not an upstream NF-kappaB site or a putative c-Ets located at the site of initiation. Lastly, chromatin immunoprecipitation analysis demonstrated the recruitment of FosB and JunB to the miR-155 promoter following BCR activation. These results identify key determinants of BCR-mediated signaling that lead to the induction of BIC/miR-155.

Micromanagement during the innate immune response.

JE Dahlberg — 2008-05-15T09:28:08-00:00

Science's STKE : signal transduction knowledge environment, Vol. 2007, No. 387. (22 May 2007)

The innate immune response can be initiated by the binding of various pathogen-associated compounds or cytokines to receptors on the surfaces of dendritic cells. These interactions result in the activation of many genes and gene products. Several different pathways converge to raise the abundance of specific microRNAs (miRNAs). In particular, activation of the transcription factors AP-1 and NF-kappaB results in an increase in the amount of miR-155. High levels of this miRNA are associated with several types of cancer. However, the mRNAs that may be targeted by miR-155 in the innate immune response remain to be determined.

A microRNA mediates EGF receptor signaling and promotes photoreceptor differentiation in the Drosophila eye.

X Li — 2006-07-11T06:29:25-00:00

Cell, Vol. 123, No. 7. (29 December 2005), pp. 1267-1277.

A critical question about signal transduction is how weak or transient activation of signaling pathways achieves a robust and long-term switch in gene expression. We report that a microRNA is part of a mechanism that makes cells sensitive to signals in the Drosophila eye. Expression of miR-7 is activated in cells as they begin differentiating into photoreceptors. This is dependent on EGF receptor (EGFR) signaling that triggers ERK-mediated degradation of the transcription factor Yan. In nonstimulated cells, Yan represses miR-7 transcription, whereas miR-7 RNA represses Yan protein expression in photoreceptors, by binding to sequences within its mRNA 3'UTR. We propose that reciprocal negative feedback between Yan and miR-7 ensures mutually exclusive expression, with Yan in progenitor cells and miR-7 in photoreceptor cells. Expression is switched when EGFR signaling transiently triggers Yan degradation. This two-tiered mechanism explains how signal transduction activity can robustly generate a stable change in gene-expression patterns.

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

Robert J Johnston Jr — 2005-11-18T15:25:34-00:00

Development (16 November 2005)

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.

MicroRNAs act sequentially and asymmetrically to control chemosensory laterality in the nematode

Sarah Chang — 2006-02-03T09:51:55-00:00

Nature, Vol. 430, No. 7001. (2004), pp. 785-789.

microRNA miR-14 acts to modulate a positive autoregulatory loop controlling steroid hormone signaling in Drosophila

Jishy Varghese — 2008-05-14T15:51:43-00:00

Genes Dev., Vol. 21, No. 18. (15 September 2007), pp. 2277-2282.

The insect steroid hormone Ecdysone and its receptor play important roles during development and metamorphosis and regulate adult physiology and life span. Ecdysone signaling, via the Ecdysone receptor (EcR), has been proposed to act in a positive autoregulatory loop to increase EcR levels and sensitize the animal to ecdysone pulses. Here we present evidence that this involves EcR-dependent transcription of the EcR gene, and that the microRNA miR-14 modulates this loop by limiting expression of its target EcR. Ecdysone signaling, via EcR, down-regulates miR-14. This alleviates miR-14-mediated repression of EcR and amplifies the response. Failure to limit EcR levels is responsible for the many of the defects observed in miR-14 mutants. miR-14 plays a key role in modulating the positive autoregulatory loop by which Ecdysone sensitizes its own signaling pathway. 10.1101/gad.439807

Control of stress-dependent cardiac growth and gene expression by a MicroRNA.

E van Rooij — 2007-05-17T13:14:29-00:00

Science, Vol. 316, No. 5824. (27 April 2007), pp. 575-579.

The heart responds to diverse forms of stress by hypertrophic growth accompanied by fibrosis and eventual diminution of contractility, which results from down-regulation of alpha-myosin heavy chain (alphaMHC) and up-regulation of betaMHC, the primary contractile proteins of the heart. We found that a cardiac-specific microRNA (miR-208) encoded by an intron of the alphaMHC gene is required for cardiomyocyte hypertrophy, fibrosis, and expression of betaMHC in response to stress and hypothyroidism. Thus, the alphaMHC gene, in addition to encoding a major cardiac contractile protein, regulates cardiac growth and gene expression in response to stress and hormonal signaling through miR-208.

MicroRNA control of Nodal signalling

Graziano Martello — 2007-08-30T16:31:30-00:00

Nature (29 August 2007)