PLoS Computational Biology

Publishing science
  • Mesoscopic Segregation of Excitation and Inhibition in a Brain Network Model
    [Feb 2015]

    by Daniel Malagarriga, Alessandro E. P. Villa, Jordi Garcia-Ojalvo, Antonio J. Pons

    Neurons in the brain are known to operate under a careful balance of excitation and inhibition, which maintains neural microcircuits within the proper operational range. How this balance is played out at the mesoscopic level of neuronal populations is, however, less clear. In order to address this issue, here we use a coupled neural mass model to study computationally the dynamics of a network of cortical macrocolumns operating in a partially synchronized, irregular regime. The topology of the network is heterogeneous, with a few of the nodes acting as connector hubs while the rest are relatively poorly connected. Our results show that in this type of mesoscopic network excitation and inhibition spontaneously segregate, with some columns acting mainly in an excitatory manner while some others have predominantly an inhibitory effect on their neighbors. We characterize the conditions under which this segregation arises, and relate the character of the different columns with their topological role within the network. In particular, we show that the connector hubs are preferentially inhibitory, the more so the larger the node's connectivity. These results suggest a potential mesoscale organization of the excitation-inhibition balance in brain networks.
    Categories: Journal Articles
  • Developing a Molecular Roadmap of Drug-Food Interactions
    [Feb 2015]

    by Kasper Jensen, Yueqiong Ni, Gianni Panagiotou, Irene Kouskoumvekaki

    Recent research has demonstrated that consumption of food -especially fruits and vegetables- can alter the effects of drugs by interfering either with their pharmacokinetic or pharmacodynamic processes. Despite the recognition of such drug-food associations as an important element for successful therapeutic interventions, a systematic approach for identifying, predicting and preventing potential interactions between food and marketed or novel drugs is not yet available. The overall objective of this work was to sketch a comprehensive picture of the interference of ∼ 4,000 dietary components present in ∼1800 plant-based foods with the pharmacokinetics and pharmacodynamics processes of medicine, with the purpose of elucidating the molecular mechanisms involved. By employing a systems chemical biology approach that integrates data from the scientific literature and online databases, we gained a global view of the associations between diet and dietary molecules with drug targets, metabolic enzymes, drug transporters and carriers currently deposited in DrugBank. Moreover, we identified disease areas and drug targets that are most prone to the negative effects of drug-food interactions, showcasing a platform for making recommendations in relation to foods that should be avoided under certain medications. Lastly, by investigating the correlation of gene expression signatures of foods and drugs we were able to generate a completely novel drug-diet interactome map.
    Categories: Journal Articles
  • Communication over the Network of Binary Switches Regulates the Activation of A2A Adenosine Receptor
    [Feb 2015]

    by Yoonji Lee, Sun Choi, Changbong Hyeon

    Dynamics and functions of G-protein coupled receptors (GPCRs) are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total ~ 5 μsec molecular dynamics simulations of A2A adenosine receptor (A2AAR) in its apo, antagonist-bound, and agonist-bound forms in an explicit water and membrane environment, and examined the corresponding dynamics and correlation between the 10 key structural motifs that serve as the allosteric hotspots in intramolecular signaling network. We dubbed these 10 structural motifs “binary switches” as they display molecular interactions that switch between two distinct states. By projecting the receptor dynamics on these binary switches that yield 210 microstates, we show that (i) the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii) among the three receptor states the apo state explores the broadest range of microstates; (iii) in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv) to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation. Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.
    Categories: Journal Articles
  • Ethical Challenges of Big Data in Public Health
    [Feb 2015]

    by Effy Vayena, Marcel Salathé, Lawrence C. Madoff, John S. Brownstein

    Categories: Journal Articles
  • Cell Cycle Control by a Minimal Cdk Network
    [Feb 2015]

    by Claude Gérard, John J. Tyson, Damien Coudreuse, Béla Novák

    In present-day eukaryotes, the cell division cycle is controlled by a complex network of interacting proteins, including members of the cyclin and cyclin-dependent protein kinase (Cdk) families, and the Anaphase Promoting Complex (APC). Successful progression through the cell cycle depends on precise, temporally ordered regulation of the functions of these proteins. In light of this complexity, it is surprising that in fission yeast, a minimal Cdk network consisting of a single cyclin-Cdk fusion protein can control DNA synthesis and mitosis in a manner that is indistinguishable from wild type. To improve our understanding of the cell cycle regulatory network, we built and analysed a mathematical model of the molecular interactions controlling the G1/S and G2/M transitions in these minimal cells. The model accounts for all observed properties of yeast strains operating with the fusion protein. Importantly, coupling the model’s predictions with experimental analysis of alternative minimal cells, we uncover an explanation for the unexpected fact that elimination of inhibitory phosphorylation of Cdk is benign in these strains while it strongly affects normal cells. Furthermore, in the strain without inhibitory phosphorylation of the fusion protein, the distribution of cell size at division is unusually broad, an observation that is accounted for by stochastic simulations of the model. Our approach provides novel insights into the organization and quantitative regulation of wild type cell cycle progression. In particular, it leads us to propose a new mechanistic model for the phenomenon of mitotic catastrophe, relying on a combination of unregulated, multi-cyclin-dependent Cdk activities.
    Categories: Journal Articles
  • Embryonic Stem Cell Specific “Master” Replication Origins at the Heart of the Loss of Pluripotency
    [Feb 2015]

    by Hanna Julienne, Benjamin Audit, Alain Arneodo

    Epigenetic regulation of the replication program during mammalian cell differentiation remains poorly understood. We performed an integrative analysis of eleven genome-wide epigenetic profiles at 100 kb resolution of Mean Replication Timing (MRT) data in six human cell lines. Compared to the organization in four chromatin states shared by the five somatic cell lines, embryonic stem cell (ESC) line H1 displays (i) a gene-poor but highly dynamic chromatin state (EC4) associated to histone variant H2AZ rather than a HP1-associated heterochromatin state (C4) and (ii) a mid-S accessible chromatin state with bivalent gene marks instead of a polycomb-repressed heterochromatin state. Plastic MRT regions (≲ 20% of the genome) are predominantly localized at the borders of U-shaped timing domains. Whereas somatic-specific U-domain borders are gene-dense GC-rich regions, 31.6% of H1-specific U-domain borders are early EC4 regions enriched in pluripotency transcription factors NANOG and OCT4 despite being GC poor and gene deserts. Silencing of these ESC-specific “master” replication initiation zones during differentiation corresponds to a loss of H2AZ and an enrichment in H3K9me3 mark characteristic of late replicating C4 heterochromatin. These results shed a new light on the epigenetically regulated global chromatin reorganization that underlies the loss of pluripotency and lineage commitment.
    Categories: Journal Articles
  • HIV Competition Dynamics over Sexual Networks: First Comer Advantage Conserves Founder Effects
    [Feb 2015]

    by Bence Ferdinandy, Enys Mones, Tamás Vicsek, Viktor Müller

    Outside Africa, the global phylogeography of HIV is characterized by compartmentalized local epidemics that are typically dominated by a single subtype, which indicates strong founder effects. We hypothesized that the competition of viral strains at the epidemic level may involve an advantage of the resident strain that was the first to colonize a population. Such an effect would slow down the invasion of new strains, and thus also the diversification of the epidemic. We developed a stochastic modelling framework to simulate HIV epidemics over dynamic contact networks. We simulated epidemics in which the second strain was introduced into a population where the first strain had established a steady-state epidemic, and assessed whether, and on what time scale, the second strain was able to spread in the population. Simulations were parameterized based on empirical data; we tested scenarios with varying levels of overall prevalence. The spread of the second strain occurred on a much slower time scale compared with the initial expansion of the first strain. With strains of equal transmission efficiency, the second strain was unable to invade on a time scale relevant for the history of the HIV pandemic. To become dominant over a time scale of decades, the second strain needed considerable (>25%) advantage in transmission efficiency over the resident strain. The inhibition effect was weaker if the second strain was introduced while the first strain was still in its growth phase. We also tested how possible mechanisms of interference (inhibition of superinfection, depletion of highly connected hubs in the network, one-time acute peak of infectiousness) contribute to the inhibition effect. Our simulations confirmed a strong first comer advantage in the competition dynamics of HIV at the population level, which may explain the global phylogeography of the virus and may influence the future evolution of the pandemic.
    Categories: Journal Articles
  • A Quick Guide for Building a Successful Bioinformatics Community
    [Feb 2015]

    by Aidan Budd, Manuel Corpas, Michelle D. Brazas, Jonathan C. Fuller, Jeremy Goecks, Nicola J. Mulder, Magali Michaut, B. F. Francis Ouellette, Aleksandra Pawlik, Niklas Blomberg

    “Scientific community” refers to a group of people collaborating together on scientific-research-related activities who also share common goals, interests, and values. Such communities play a key role in many bioinformatics activities. Communities may be linked to a specific location or institute, or involve people working at many different institutions and locations. Education and training is typically an important component of these communities, providing a valuable context in which to develop skills and expertise, while also strengthening links and relationships within the community. Scientific communities facilitate: (i) the exchange and development of ideas and expertise; (ii) career development; (iii) coordinated funding activities; (iv) interactions and engagement with professionals from other fields; and (v) other activities beneficial to individual participants, communities, and the scientific field as a whole. It is thus beneficial at many different levels to understand the general features of successful, high-impact bioinformatics communities; how individual participants can contribute to the success of these communities; and the role of education and training within these communities. We present here a quick guide to building and maintaining a successful, high-impact bioinformatics community, along with an overview of the general benefits of participating in such communities. This article grew out of contributions made by organizers, presenters, panelists, and other participants of the ISMB/ECCB 2013 workshop “The ‘How To Guide’ for Establishing a Successful Bioinformatics Network” at the 21st Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) and the 12th European Conference on Computational Biology (ECCB).
    Categories: Journal Articles
  • When Less Is More: Non-monotonic Spike Sequence Processing in Neurons
    [Feb 2015]

    by Hinrich Arnoldt, Shuwen Chang, Sven Jahnke, Birk Urmersbach, Holger Taschenberger, Marc Timme

    Fundamental response properties of neurons centrally underly the computational capabilities of both individual nerve cells and neural networks. Most studies on neuronal input-output relations have focused on continuous-time inputs such as constant or noisy sinusoidal currents. Yet, most neurons communicate via exchanging action potentials (spikes) at discrete times. Here, we systematically analyze the stationary spiking response to regular spiking inputs and reveal that it is generically non-monotonic. Our theoretical analysis shows that the underlying mechanism relies solely on a combination of the discrete nature of the communication by spikes, the capability of locking output to input spikes and limited resources required for spike processing. Numerical simulations of mathematically idealized and biophysically detailed models, as well as neurophysiological experiments confirm and illustrate our theoretical predictions.
    Categories: Journal Articles
  • Exploring Bacterial Organelle Interactomes: A Model of the Protein-Protein Interaction Network in the Pdu Microcompartment
    [Feb 2015]

    by Julien Jorda, Yu Liu, Thomas A. Bobik, Todd O. Yeates

    Bacterial microcompartments (MCPs) are protein-bound organelles that carry out diverse metabolic pathways in a wide range of bacteria. These supramolecular assemblies consist of a thin outer protein shell, reminiscent of a viral capsid, which encapsulates sequentially acting enzymes. The most complex MCP elucidated so far is the propanediol utilizing (Pdu) microcompartment. It contains the reactions for degrading 1,2-propanediol. While several experimental studies on the Pdu system have provided hints about its organization, a clear picture of how all the individual components interact has not emerged yet. Here we use co-evolution-based methods, involving pairwise comparisons of protein phylogenetic trees, to predict the protein-protein interaction (PPI) network governing the assembly of the Pdu MCP. We propose a model of the Pdu interactome, from which selected PPIs are further inspected via computational docking simulations. We find that shell protein PduA is able to serve as a “universal hub” for targeting an array of enzymes presenting special N-terminal extensions, namely PduC, D, E, L and P. The varied N-terminal peptides are predicted to bind in the same cleft on the presumptive luminal face of the PduA hexamer. We also propose that PduV, a protein of unknown function with remote homology to the Ras-like GTPase superfamily, is likely to localize outside the MCP, interacting with the protruding β-barrel of the hexameric PduU shell protein. Preliminary experiments involving a bacterial two-hybrid assay are presented that corroborate the existence of a PduU-PduV interaction. This first systematic computational study aimed at characterizing the interactome of a bacterial microcompartment provides fresh insight into the organization of the Pdu MCP.
    Categories: Journal Articles
  • Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial
    [Feb 2015]

    by Paul T. Edlefsen, Morgane Rolland, Tomer Hertz, Sodsai Tovanabutra, Andrew J. Gartland, Allan C. deCamp, Craig A. Magaret, Hasan Ahmed, Raphael Gottardo, Michal Juraska, Connor McCoy, Brendan B. Larsen, Eric Sanders-Buell, Chris Carrico, Sergey Menis, Meera Bose, RV144 Sequencing Team , Miguel A. Arroyo, Robert J. O’Connell, Sorachai Nitayaphan, Punnee Pitisuttithum, Jaranit Kaewkungwal, Supachai Rerks-Ngarm, Merlin L. Robb, Tatsiana Kirys, Ivelin S. Georgiev, Peter D. Kwong, Konrad Scheffler, Sergei L. Kosakovsky Pond, Jonathan M. Carlson, Nelson L. Michael, William R. Schief, James I. Mullins, Jerome H. Kim, Peter B. Gilbert

    The RV144 clinical trial showed the partial efficacy of a vaccine regimen with an estimated vaccine efficacy (VE) of 31% for protecting low-risk Thai volunteers against acquisition of HIV-1. The impact of vaccine-induced immune responses can be investigated through sieve analysis of HIV-1 breakthrough infections (infected vaccine and placebo recipients). A V1/V2-targeted comparison of the genomes of HIV-1 breakthrough viruses identified two V2 amino acid sites that differed between the vaccine and placebo groups. Here we extended the V1/V2 analysis to the entire HIV-1 genome using an array of methods based on individual sites, k-mers and genes/proteins. We identified 56 amino acid sites or “signatures” and 119 k-mers that differed between the vaccine and placebo groups. Of those, 19 sites and 38 k-mers were located in the regions comprising the RV144 vaccine (Env-gp120, Gag, and Pro). The nine signature sites in Env-gp120 were significantly enriched for known antibody-associated sites (p = 0.0021). In particular, site 317 in the third variable loop (V3) overlapped with a hotspot of antibody recognition, and sites 369 and 424 were linked to CD4 binding site neutralization. The identified signature sites significantly covaried with other sites across the genome (mean = 32.1) more than did non-signature sites (mean = 0.9) (p < 0.0001), suggesting functional and/or structural relevance of the signature sites. Since signature sites were not preferentially restricted to the vaccine immunogens and because most of the associations were insignificant following correction for multiple testing, we predict that few of the genetic differences are strongly linked to the RV144 vaccine-induced immune pressure. In addition to presenting results of the first complete-genome analysis of the breakthrough infections in the RV144 trial, this work describes a set of statistical methods and tools applicable to analysis of breakthrough infection genomes in general vaccine efficacy trials for diverse pathogens.
    Categories: Journal Articles
  • GenomicScape: An Easy-to-Use Web Tool for Gene Expression Data Analysis. Application to Investigate the Molecular Events in the Differentiation of B Cells into Plasma Cells
    [Jan 2015]

    by Alboukadel Kassambara, Thierry Rème, Michel Jourdan, Thierry Fest, Dirk Hose, Karin Tarte, Bernard Klein

    DNA microarrays have considerably helped to improve the understanding of biological processes and diseases. Large amounts of publicly available microarray data are accumulating, but are poorly exploited due to a lack of easy-to-use bioinformatics resources. The aim of this study is to build a free and convenient data-mining web site (www.genomicscape.com). GenomicScape allows mining dataset from various microarray platforms, identifying genes differentially expressed between populations, clustering populations, visualizing expression profiles of large sets of genes, and exporting results and figures. We show how easily GenomicScape makes it possible to construct a molecular atlas of the B cell differentiation using publicly available transcriptome data of naïve B cells, centroblasts, centrocytes, memory B cells, preplasmablasts, plasmablasts, early plasma cells and bone marrow plasma cells. Genes overexpressed in each population and the pathways encoded by these genes are provided as well as how the populations cluster together. All the analyses, tables and figures can be easily done and exported using GenomicScape and this B cell to plasma cell atlas is freely available online. Beyond this B cell to plasma cell atlas, the molecular characteristics of any biological process can be easily and freely investigated by uploading the corresponding transcriptome files into GenomicScape.
    Categories: Journal Articles
  • ISCB Ebola Award for Important Future Research on the Computational Biology of Ebola Virus
    [Jan 2015]

    by Peter D. Karp, Bonnie Berger, Diane Kovats, Thomas Lengauer, Michal Linial, Pardis Sabeti, Winston Hide, Burkhard Rost

    Speed is of the essence in combating Ebola; thus, computational approaches should form a significant component of Ebola research. As for the development of any modern drug, computational biology is uniquely positioned to contribute through comparative analysis of the genome sequences of Ebola strains as well as 3-D protein modeling. Other computational approaches to Ebola may include large-scale docking studies of Ebola proteins with human proteins and with small-molecule libraries, computational modeling of the spread of the virus, computational mining of the Ebola literature, and creation of a curated Ebola database. Taken together, such computational efforts could significantly accelerate traditional scientific approaches. In recognition of the need for important and immediate solutions from the field of computational biology against Ebola, the International Society for Computational Biology (ISCB) announces a prize for an important computational advance in fighting the Ebola virus. ISCB will confer the ISCB Fight against Ebola Award, along with a prize of US$2,000, at its July 2016 annual meeting (ISCB Intelligent Systems for Molecular Biology [ISMB] 2016, Orlando, Florida).
    Categories: Journal Articles
  • Ten Simple Rules for Organizing an Unconference
    [Jan 2015]

    by Aidan Budd, Holger Dinkel, Manuel Corpas, Jonathan C. Fuller, Laura Rubinat, Damien P. Devos, Pierre H. Khoueiry, Konrad U. Förstner, Fotis Georgatos, Francis Rowland, Malvika Sharan, Janos X. Binder, Tom Grace, Karyn Traphagen, Adam Gristwood, Natasha T. Wood

    Categories: Journal Articles
  • Computation in Dynamically Bounded Asymmetric Systems
    [Jan 2015]

    by Ueli Rutishauser, Jean-Jacques Slotine, Rodney Douglas

    Previous explanations of computations performed by recurrent networks have focused on symmetrically connected saturating neurons and their convergence toward attractors. Here we analyze the behavior of asymmetrical connected networks of linear threshold neurons, whose positive response is unbounded. We show that, for a wide range of parameters, this asymmetry brings interesting and computationally useful dynamical properties. When driven by input, the network explores potential solutions through highly unstable ‘expansion’ dynamics. This expansion is steered and constrained by negative divergence of the dynamics, which ensures that the dimensionality of the solution space continues to reduce until an acceptable solution manifold is reached. Then the system contracts stably on this manifold towards its final solution trajectory. The unstable positive feedback and cross inhibition that underlie expansion and divergence are common motifs in molecular and neuronal networks. Therefore we propose that very simple organizational constraints that combine these motifs can lead to spontaneous computation and so to the spontaneous modification of entropy that is characteristic of living systems.
    Categories: Journal Articles
  • Laminar and Dorsoventral Molecular Organization of the Medial Entorhinal Cortex Revealed by Large-scale Anatomical Analysis of Gene Expression
    [Jan 2015]

    by Helen L. Ramsden, Gülşen Sürmeli, Steven G. McDonagh, Matthew F. Nolan

    Neural circuits in the medial entorhinal cortex (MEC) encode an animal’s position and orientation in space. Within the MEC spatial representations, including grid and directional firing fields, have a laminar and dorsoventral organization that corresponds to a similar topography of neuronal connectivity and cellular properties. Yet, in part due to the challenges of integrating anatomical data at the resolution of cortical layers and borders, we know little about the molecular components underlying this organization. To address this we develop a new computational pipeline for high-throughput analysis and comparison of in situ hybridization (ISH) images at laminar resolution. We apply this pipeline to ISH data for over 16,000 genes in the Allen Brain Atlas and validate our analysis with RNA sequencing of MEC tissue from adult mice. We find that differential gene expression delineates the borders of the MEC with neighboring brain structures and reveals its laminar and dorsoventral organization. We propose a new molecular basis for distinguishing the deep layers of the MEC and show that their similarity to corresponding layers of neocortex is greater than that of superficial layers. Our analysis identifies ion channel-, cell adhesion- and synapse-related genes as candidates for functional differentiation of MEC layers and for encoding of spatial information at different scales along the dorsoventral axis of the MEC. We also reveal laminar organization of genes related to disease pathology and suggest that a high metabolic demand predisposes layer II to neurodegenerative pathology. In principle, our computational pipeline can be applied to high-throughput analysis of many forms of neuroanatomical data. Our results support the hypothesis that differences in gene expression contribute to functional specialization of superficial layers of the MEC and dorsoventral organization of the scale of spatial representations.
    Categories: Journal Articles
  • A Probabilistic Palimpsest Model of Visual Short-term Memory
    [Jan 2015]

    by Loic Matthey, Paul M. Bays, Peter Dayan

    Working memory plays a key role in cognition, and yet its mechanisms remain much debated. Human performance on memory tasks is severely limited; however, the two major classes of theory explaining the limits leave open questions about key issues such as how multiple simultaneously-represented items can be distinguished. We propose a palimpsest model, with the occurrent activity of a single population of neurons coding for several multi-featured items. Using a probabilistic approach to storage and recall, we show how this model can account for many qualitative aspects of existing experimental data. In our account, the underlying nature of a memory item depends entirely on the characteristics of the population representation, and we provide analytical and numerical insights into critical issues such as multiplicity and binding. We consider representations in which information about individual feature values is partially separate from the information about binding that creates single items out of multiple features. An appropriate balance between these two types of information is required to capture fully the different types of error seen in human experimental data. Our model provides the first principled account of misbinding errors. We also suggest a specific set of stimuli designed to elucidate the representations that subjects actually employ.
    Categories: Journal Articles
  • A New Algorithm to Diagnose Atrial Ectopic Origin from Multi Lead ECG Systems - Insights from 3D Virtual Human Atria and Torso
    [Jan 2015]

    by Erick A. Perez Alday, Michael A. Colman, Philip Langley, Timothy D. Butters, Jonathan Higham, Antony J. Workman, Jules C. Hancox, Henggui Zhang

    Rapid atrial arrhythmias such as atrial fibrillation (AF) predispose to ventricular arrhythmias, sudden cardiac death and stroke. Identifying the origin of atrial ectopic activity from the electrocardiogram (ECG) can help to diagnose the early onset of AF in a cost-effective manner. The complex and rapid atrial electrical activity during AF makes it difficult to obtain detailed information on atrial activation using the standard 12-lead ECG alone. Compared to conventional 12-lead ECG, more detailed ECG lead configurations may provide further information about spatio-temporal dynamics of the body surface potential (BSP) during atrial excitation. We apply a recently developed 3D human atrial model to simulate electrical activity during normal sinus rhythm and ectopic pacing. The atrial model is placed into a newly developed torso model which considers the presence of the lungs, liver and spinal cord. A boundary element method is used to compute the BSP resulting from atrial excitation. Elements of the torso mesh corresponding to the locations of the placement of the electrodes in the standard 12-lead and a more detailed 64-lead ECG configuration were selected. The ectopic focal activity was simulated at various origins across all the different regions of the atria. Simulated BSP maps during normal atrial excitation (i.e. sinoatrial node excitation) were compared to those observed experimentally (obtained from the 64-lead ECG system), showing a strong agreement between the evolution in time of the simulated and experimental data in the P-wave morphology of the ECG and dipole evolution. An algorithm to obtain the location of the stimulus from a 64-lead ECG system was developed. The algorithm presented had a success rate of 93%, meaning that it correctly identified the origin of atrial focus in 75/80 simulations, and involved a general approach relevant to any multi-lead ECG system. This represents a significant improvement over previously developed algorithms.
    Categories: Journal Articles
  • A Computational Approach to Identifying Gene-microRNA Modules in Cancer
    [Jan 2015]

    by Daeyong Jin, Hyunju Lee

    MicroRNAs (miRNAs) play key roles in the initiation and progression of various cancers by regulating genes. Regulatory interactions between genes and miRNAs are complex, as multiple miRNAs can regulate multiple genes. In addtion, these interactions vary from patient to patient and even among patients with the same cancer type, as cancer development is a heterogeneous process. These relationships are more complicated because transcription factors and other regulatory molecules can also regulate miRNAs and genes. Hence, it is important to identify the complex relationships between genes and miRNAs in cancer. In this study, we propose a computational approach to constructing modules that represent these relationships by integrating the expression data of genes and miRNAs with gene-gene interaction data. First, we used a biclustering algorithm to construct modules consisting of a subset of genes and a subset of samples to incorporate the heterogeneity of cancer cells. Second, we combined gene-gene interactions to include genes that play important roles in cancer-related pathways. Then, we selected miRNAs that are closely associated with genes in the modules based on a Gaussian Bayesian network and Bayesian Information Criteria. When we applied our approach to ovarian cancer and glioblastoma (GBM) data sets, 33 and 54 modules were constructed, respectively. In these modules, 91% and 94% of ovarian cancer and GBM modules, respectively, were explained either by direct regulation between genes and miRNAs or by indirect relationships via transcription factors. In addition, 48.4% and 74.0% of modules from ovarian cancer and GBM, respectively, were enriched with cancer-related pathways, and 51.7% and 71.7% of miRNAs in modules were ovarian cancer-related miRNAs and GBM-related miRNAs, respectively. Finally, we extensively analyzed significant modules and showed that most genes in these modules were related to ovarian cancer and GBM.
    Categories: Journal Articles