Articles Online (Volume 10, Issue 5)

Preface

MicroRNAs: Mechanisms, Functions and Progress

Tongbin Li ,William C.S. Cho

Page 237–238


Review

Biogenesis of Mammalian MicroRNAs: A Global View

Paul Graves ,Yan Zeng

MicroRNAs (miRNAs) are approximately 22-nucleotide-long non-coding RNAs that are important regulators of gene expression in eukaryotes. miRNAs are first transcribed as long primary transcripts, which then undergo a series of processing steps to produce the single-stranded mature miRNAs. This article reviews our current knowledge of the mechanism and regulation of mammalian miRNA expression and points out areas of research that may enhance our understanding of how the specificity and efficiency of miRNA production is controlled in vivo.

Page 239–245


Review

MicroRNAs in Common Human Diseases

Yu Li ,Kris V. Kowdley

MicroRNAs (miRNAs) are a class of short non-coding RNA molecules that have attracted tremendous attention from the biological and biomedical research communities over the past decade. With over 1900 miRNAs discovered in humans to date, many of them have already been implicated in common human disorders. Facilitated by high-throughput genomics and bioinformatics in conjunction with traditional molecular biology techniques and animal models, miRNA research is now positioned to make the transition from laboratories to clinics to deliver profound benefits to public health. Herein, we overview the progress of miRNA research related to human diseases, as well as the potential for miRNA to becoming the next generation of diagnostics and therapeutics.

Page 246–253


Review

One Decade of Development and Evolution of MicroRNA Target Prediction Algorithms

Paula H. Reyes∼Herrera ,Elisa Ficarra

Nearly two decades have passed since the publication of the first study reporting the discovery of microRNAs (miRNAs). The key role of miRNAs in post-transcriptional gene regulation led to the performance of an increasing number of studies focusing on origins, mechanisms of action and functionality of miRNAs. In order to associate each miRNA to a specific functionality it is essential to unveil the rules that govern miRNA action. Despite the fact that there has been significant improvement exposing structural characteristics of the miRNA–mRNA interaction, the entire physical mechanism is not yet fully understood. In this respect, the development of computational algorithms for miRNA target prediction becomes increasingly important. This manuscript summarizes the research done on miRNA target prediction. It describes the experimental data currently available and used in the field and presents three lines of computational approaches for target prediction. Finally, the authors put forward a number of considerations regarding current challenges and future directions.

Page 254–263


Review

Finding MicroRNA Targets in Plants: Current Status and Perspectives

Jiandong Ding , Shuigeng Zhou , Jihong Guan

MicroRNAs (miRNAs), a class of ∼20–24 nt long non-coding RNAs, have critical roles in diverse biological processes including development, proliferation, stress response, etc. With the development and availability of experimental technologies and computational approaches, the field of miRNA biology has advanced tremendously over the last decade. By sequence complementarity, miRNAs have been estimated to regulate certain mRNA transcripts. Although it was once thought to be simple and straightforward to find plant miRNA targets, this viewpoint is being challenged by genetic and biochemical studies. In this review, we summarize recent progress in plant miRNA target recognition mechanisms, principles of target prediction, and introduce current experimental and computational tools for plant miRNA target prediction. At the end, we also present our thinking on the outlook for future directions in the development of plant miRNA target finding methods.

Page 264–275


Review

Predicting sRNAs and Their Targets in Bacteria

Wuju Li, Xiaomin Ying, Qixuan Lu, Linxi Chen

Bacterial small RNAs (sRNAs) are an emerging class of regulatory RNAs of about 40–500 nucleotides in length and, by binding to their target mRNAs or proteins, get involved in many biological processes such as sensing environmental changes and regulating gene expression. Thus, identification of bacterial sRNAs and their targets has become an important part of sRNA biology. Current strategies for discovery of sRNAs and their targets usually involve bioinformatics prediction followed by experimental validation, emphasizing a key role for bioinformatics prediction. Here, therefore, we provided an overview on prediction methods, focusing on the merits and limitations of each class of models. Finally, we will present our thinking on developing related bioinformatics models in future.

Page 276–284


Original Research

Whole miRNome-wide Differential Co-expression of MicroRNAs

Cord F. Stäehler, Andreas Keller, Petra Leidinger, Christina Backes, Anoop Chandran, Jöerg Wischhusen, Benjamin Meder, Eckart Meese

Co-regulation of genes has been extensively analyzed, however, rather limited knowledge is available on co-regulations within the miRNome. We investigated differential co-expression of microRNAs (miRNAs) based on miRNome profiles of whole blood from 540 individuals. These include patients suffering from different cancer and non-cancer diseases, and unaffected controls. Using hierarchical clustering, we found 9 significant clusters of co-expressed miRNAs containing 2–36 individual miRNAs. Through analyzing multiple sequencing alignments in the clusters, we found that co-expression of miRNAs is associated with both sequence similarity and genomic co-localization. We calculated correlations for all 371,953 pairs of miRNAs for all 540 individuals and identified 184 pairs of miRNAs with high correlation values. Out of these 184 pairs of miRNAs, 16 pairs (8.7%) were differentially co-expressed in unaffected controls, cancer patients and patients with non-cancer diseases. By computing correlated and anti-correlated miRNA pairs, we constructed a network with 184 putative co-regulations as edges and 100 miRNAs as nodes. Thereby, we detected specific clusters of miRNAs with high and low correlation values. Our approach represents the most comprehensive co-regulation analysis based on whole miRNome-wide expression profiling. Our findings further decrypt the interactions of miRNAs in normal and human pathological processes.

Page 285–294


Original Research

Differential Expression of Mature MicroRNAs Involved in Muscle Maintenance of Hibernating Little Brown Bats, Myotis lucifugus: A Model of Muscle Atrophy Resistance

Samantha F. Kornfeld, Kyle K. Biggar, Kenneth B. Storey

Muscle wasting is common in mammals during extended periods of immobility. However, many small hibernating mammals manage to avoid muscle atrophy despite remaining stationary for long periods during hibernation. Recent research has highlighted roles for short non-coding microRNAs (miRNAs) in the regulation of stress tolerance. We proposed that they could also play an important role in muscle maintenance during hibernation. To explore this possibility, a group of 10 miRNAs known to be normally expressed in skeletal muscle of non-hibernating mammals were analyzed by RT-PCR in hibernating little brown bats, Myotis lucifugus. We then compared the expression of these miRNAs in euthermic control bats and bats in torpor. Our results showed that compared to euthermic controls, significant, albeit modest (1.2–1.6 fold), increases in transcript expression were observed for eight mature miRNAs, including miR-1a-1, miR-29b, miR-181b, miR-15a, miR-20a, miR-206 and miR-128-1, in the pectoral muscle of torpid bats. Conversely, expression of miR-21 decreased by 80% during torpor, while expression of miR-107 remained unaffected. Interestingly, these miRNAs have been either validated or predicted to affect multiple muscle-specific factors, including myostatin, FoxO3a, HDAC4 and SMAD7, and are likely involved in the preservation of pectoral muscle mass and functionality during bat hibernation.

Page 295–301


Original Research

MicroRNA Regulation in Extreme Environments: Differential Expression of MicroRNAs in the Intertidal Snail Littorina littorea During Extended Periods of Freezing and Anoxia

Kyle K. Biggar, Samantha F. Kornfeld, Yulia Maistrovski, Kenneth B. Storey

Several recent studies of vertebrate adaptation to environmental stress have suggested roles for microRNAs (miRNAs) in regulating global suppression of protein synthesis and/or restructuring protein expression patterns. The present study is the first to characterize stress-responsive alterations in the expression of miRNAs during natural freezing or anoxia exposures in an invertebrate species, the intertidal gastropod Littorina littorea. These snails are exposed to anoxia and freezing conditions as their environment constantly fluctuates on both a tidal and seasonal basis. The expression of selected miRNAs that are known to influence the cell cycle, cellular signaling pathways, carbohydrate metabolism and apoptosis was evaluated using RT-PCR. Compared to controls, significant changes in expression were observed for miR-1a-1, miR-34a and miR-29b in hepatopancreas and for miR-1a-1, miR-34a, miR-133a, miR-125b, miR-29b and miR-2a in foot muscle after freezing exposure at −6 °C for 24 h (P < 0.05). In addition, in response to anoxia stress for 24 h, significant changes in expression were also observed for miR-1a-1, miR-210 and miR-29b in hepatopancreas and for miR-1a-1, miR-34a, miR-133a, miR-29b and miR-2a in foot muscle (P < 0.05). Moreover, protein expression of Dicer, an enzyme responsible for mature microRNA processing, was increased in foot muscle during freezing and anoxia and in hepatopancreas during freezing. Alterations in expression of these miRNAs in L. littorea tissues may contribute to organismal survival under freezing and anoxia.

Page 302–309


Method

miRT: A Database of Validated Transcription Start Sites of Human MicroRNAs

Malay Bhattacharyya, Manali Das, Sanghamitra Bandyopadhyay

MicroRNAs (miRNAs) are small endogenous non-coding RNAs of about 22 nt in length that take crucial roles in many biological processes. These short RNAs regulate the expression of mRNAs by binding to their 3′-UTRs or by translational repression. Many of the current studies focus on how mature miRNAs regulate mRNAs, however, very limited knowledge is available regarding their transcriptional loci. It is known that primary miRNAs (pri-miRs) are first transcribed from the DNA, followed by the formation of precursor miRNAs (pre-miRs) by endonuclease activity, which finally produces the mature miRNAs. Till date, many of the pre-miRs and mature miRNAs have been experimentally verified. But unfortunately, identification of the loci of pri-miRs, promoters and associated transcription start sites (TSSs) are still in progress. TSSs of only about 40% of the known mature miRNAs in human have been reported. This information, albeit limited, may be useful for further study of the regulation of miRNAs. In this paper, we provide a novel database of validated miRNA TSSs, miRT, by collecting data from several experimental studies that validate miRNA TSSs and are available for full download. We present miRT as a web server and it is also possible to convert the TSS loci between different genome built. miRT might be a valuable resource for advanced research on miRNA regulation, which is freely accessible at: http://www.isical.ac.in/~bioinfo_miu/miRT/miRT.php.

Page 310–316