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Simple Shared Motifs (SSM) in conserved region of promoters: a new approach to identify co-regulation patterns
Jérémy Gruel, Michel LeBorgne, Nolwenn LeMeur, Nathalie Théret
BMC Bioinformatics , 2011, DOI: 10.1186/1471-2105-12-365
Abstract: Here, we propose a different approach based on the compilation of Simple Shared Motifs (SSM), groups of sequences defined by their length and similarity and present in conserved sequences of gene promoters. We developed an original algorithm to search and count SSM in pairs of genes. An exceptional number of SSM is considered as a common regulatory pattern. The SSM approach is applied to a sample set of genes and validated using functional gene-set enrichment analyses. We demonstrate that the SSM approach selects genes that are over-represented in specific biological categories (Ontology and Pathways) and are enriched in co-expressed genes. Finally we show that genes co-expressed in the same tissue or involved in the same biological pathway have increased SSM values.Using unbiased clustering of genes, Simple Shared Motifs analysis constitutes an original contribution to provide a clearer definition of expression networks.A major challenge for modern molecular biology consists in deciphering the complex regulation of gene expression. During the two last decades, numerous experimental and computational approaches have been developed to identify functional regulatory domains in genes. Binding sites for transcription factors (TFBS) are central elements in the modulation of transcriptional activity. These short DNA sequences are cis-regulatory motifs usually located in the proximal promoter region of target genes and bind trans-acting transcription factors [1]. Transcription factors have been shown to act cooperatively [2], leading to the emergence of the CRM (cis-regulatory modules) concept.In silico approaches designed to uncover regulatory elements in gene promoters are based on this understanding of gene regulation. A possible binary categorization of these approaches is based on the fact that they use or not previously described TFBS, stored in databases such as TRANSFAC [3] or JASPAR [4]. Both strategies have advantages and drawbacks.Although TFBS databases are adm
In silico investigation of ADAM12 effect on TGF-β receptors trafficking
Jérémy Gruel, Michel LeBorgne, Nolwenn LeMeur, Nathalie Théret
BMC Research Notes , 2009, DOI: 10.1186/1756-0500-2-193
Abstract: We extracted qualitative biological observations from experimental data and defined a family of models producing a behavior compatible with the presence of ADAM12. We computationally explored the properties of this family of models which allowed us to make novel predictions. We predict that ADAM12 increases TGF-β receptors internalization rate between the cell surface and the endosomal membrane. It also appears that ADAM12 modifies TGF-β signaling shape favoring a permanent response by removing the transient component observed under physiological conditions.In this work, confronting differential models with qualitative biological observations, we obtained predictions giving new insights into the role of ADAM12 in TGF-β signaling and hepatic fibrosis process.During chronic liver injury, the sustained wound healing response leads to fibrosis and cirrhosis. Among the molecular components involved in fibrogenesis, the transforming growth factor, TGF-β is the most potent profibrotic cytokine. Indeed, several authors have shown that alteration of TGF-β dependent signaling pathway is associated with liver fibrosis [1,2]. In this system, the first cellular control point is at the membrane. TGF-β transmits its signal through a heteromeric complex of two types of transmembrane receptors, TβRI and TβRII. TGF-β binding to TβRII induces recruitment and phosphorylation of TβRI, which activates R-Smad intracellular signaling [3]. At the membrane, an important feature of TGF-β signaling is the continuous internalization of receptors and ligand-receptor complexes through two endocytosis pathways: the clathrin-coated pit endocytosis, mediating R-Smad signaling cascade, and the caveolin mediated endocytosis, leading to degradation of receptors through the proteasome pathway [4,5].We have recently demonstrated that ADAM12, a member of the disintegrin and metalloproteinase family associated with liver fibrogenesis [6,7], facilitates TGF-β signaling at the membrane [8]. ADAM12 interacts
Knowledge based identification of essential signaling from genome-scale siRNA experiments
Armand Bankhead, Iliana Sach, Chester Ni, Nolwenn LeMeur, Mark Kruger, Marc Ferrer, Robert Gentleman, Carol Rohl
BMC Systems Biology , 2009, DOI: 10.1186/1752-0509-3-80
Abstract: We use PIPA to analyze genome-scale siRNA cell growth screens performed in HeLa and TOV cell lines. First we show that interacting gene pair siRNA hits are more reproducible than single gene hits. Using protein interactions, PIPA identifies enriched pathways not found using the standard Hypergeometric analysis including the FAK cytoskeletal remodeling pathway. Different branches of the FAK pathway are distinctly essential in HeLa versus TOV cell lines while other portions are uneffected by siRNA perturbations. Enriched hits belong to protein interactions associated with cell cycle regulation, anti-apoptosis, and signal transduction.PIPA provides an analytical framework to interpret siRNA screen data by merging biologically annotated gene sets with the human interactome. As a result we identify pathways and signaling hypotheses that are statistically enriched to effect cell growth in human cell lines. This method provides a complementary approach to standard gene set enrichment that utilizes the additional knowledge of specific interactions within biological gene sets.The ability to study a gene's contribution to phenotype through RNA interference (RNAi) has provided unprecedented insight to the essential biology of mammalian cell lines. RNAi knockdowns inhibit messenger RNA translation leading to changes in protein concentration, protein interactions, transcription, and ultimately an effect on phenotype [1-3]. Genome-scale siRNA phenotype screens consist of thousands of targeted perturbation experiments to identify significant effectors on a phenotype of interest, such as cell growth. As these high-throughput screens become more automated and less expensive, there is a growing demand to associate siRNA hits with the interactome.Unfortunately, the interpretation of genome-scale RNAi phenotype screens is complicated by several sources of experimental variability. Off-target effects arise when the change in phenotype is not a result of a targeted mRNA knockdown, but ra
flowCore: a Bioconductor package for high throughput flow cytometry
Florian Hahne, Nolwenn LeMeur, Ryan R Brinkman, Byron Ellis, Perry Haaland, Deepayan Sarkar, Josef Spidlen, Errol Strain, Robert Gentleman
BMC Bioinformatics , 2009, DOI: 10.1186/1471-2105-10-106
Abstract: We developed a set of flexible open source computational tools in the R package flowCore to facilitate the analysis of these complex data. A key component of which is having suitable data structures that support the application of similar operations to a collection of samples or a clinical cohort. In addition, our software constitutes a shared and extensible research platform that enables collaboration between bioinformaticians, computer scientists, statisticians, biologists and clinicians. This platform will foster the development of novel analytic methods for flow cytometry.The software has been applied in the analysis of various data sets and its data structures have proven to be highly efficient in capturing and organizing the analytic work flow. Finally, a number of additional Bioconductor packages successfully build on the infrastructure provided by flowCore, open new avenues for flow data analysis.Automation technologies developed during the last several years have enabled the use of flow cytometry (FCM) to generate large, complex data sets in both basic and clinical research applications [1]. A serious bottleneck in the interpretation of existing studies and the application of high throughput FCM to even larger, more complex problems is that data management and data analysis methods have not advanced sufficiently far from the methods developed for applications of FCM to small-scale, tube-based studies [2]. In particular, the data often need to be organized into groups of samples based on combinations of additional covariates and similar operations need to be applied to these groups in a transparent and reproducible manner. Furthermore, the growing depth of knowledge in the field of immunology, for instance the characterization of distinct human T-cell sub-population [3], clearly argues for more systematic approaches.Some of the consequences of the lag of efficient software solutions are difficulties in maintaining the integrity and documentation of large dat
Edgar Morin, Pierre Nora, Michel Onfray, et al., Des Intellectuels jugent les médias
Nolwenn Mingant
InMedia : the French Journal of Media and Media Representations in the English-Speaking World , 2012,
Abstract: Des intellectuels jugent les médias is a collection of interviews published in French magazine Médias over the past five years. The ‘intellectuals’ in question are renowned philosophers (Daniel Bougnoux, André Compte-Sponville, Régis Debray, Yves Michaud, Michel Onfray, the Spanish Fernando Savater), historians (Marcel Gauchet, Pierre Nora), sociologists (Edgar Morin), and essayists (Philippe Sollers, Paul Virilio). In publishing these interviews, Mordicus Editions aims to help people to ‘bet...
Hollywood’s Global Outlook: Economic Expansionism and Production Strategy La perspective mondiale d’Hollywood : expansion économique et stratégique de production
Nolwenn Mingant
Revue LISA / LISA e-journal , 2009, DOI: 10.4000/lisa.1615
Abstract: Depuis le milieu des années soixante, l’importance du marché extérieur pour les majors américaines a beaucoup varié. Marché mineur à la fin des années soixante-dix et dans les années quatre-vingt, il prend de plus en plus d’importance depuis le début des années quatre-vingt dix. L’arrivée de nouvelles technologies ainsi que l’ouverture de nouveaux territoires sont les deux phénomènes qui expliquent ce regain d’importance. Depuis le début des années quatre-vingt dix, les majors se sont donc lancées dans une nouvelle vague d’expansion économique mondiale. La question centrale de cet article est alors la suivante. Le désir qu’ont les majors hollywoodiennes d’expansion économique mondiale a-t-il une influence sur leurs choix de production, et, en particulier, a-t-il une influence sur le caractère national des films produits? En suivant pas à pas la fa on dont Hollywood observe le marché extérieur depuis quarante ans, puis sa tendance croissante à prendre en compte dans les choix de production les go ts du public étranger, nous nous poserons inévitablement la question des conséquences culturelles de ces pratiques économiques, autour des notions d’universalité, d’internationalisation et d’identité nationale, jusqu’à ce que finalement se révèle à nous une nouvelle identité hollywoodienne: Glocalwood.
Global Film and Television Industries Today: An Analysis of Industrial and Cultural Relations
Nolwenn Mingant,Cecilia Tirtaine
InMedia : the French Journal of Media and Media Representations in the English-Speaking World , 2012,
Abstract: Globalization has led to an increase in contacts between the film and television industries of different countries, particularly within the English-speaking world. The aim of this set of articles is to highlight specific issues brought about by globalization through different methodological approaches. The internationalization of film and television industries, linked to globalization, has had far-reaching consequences, from an industrial point of view, notably with the development of “runawa...
Blog : un journal intime comme mémoire de soi
Nolwenn Hénaff
Conserveries Mémorielles : Revue Transdisciplinaire de Jeunes Chercheurs , 2011,
Abstract: Tenir un journal est devenu, pour un individu, une manière possible de vivre, ou d’accompagner un moment de sa vie (Lejeune, 2006). Les usages sont donc multiples : construction d’une identité narrative, fixation du temps, libération du moi, introspection, outil de contr le, de soutien, méthode d’organisation de la pensée, plaisir d’écrire. Si l’écriture papier reste la forme la plus courante du récit biographique, d’autres supports médiatiques comme la télévision ou la radio sont venus offrir de nouveaux terrains d’expérimentation de ces récits de soi. Plus récemment, l’avènement d’Internet et de ses outils simplifiés de publication ont fait émerger des formes biographiques innovantes. Pourtant, qu’il s’agisse de traverser une crise, de garder la mémoire d’une expérience forte, ou, plus ordinairement, de relater ses vacances et ses voyages, le journal se positionne avant tout, et résolument, comme un espace de liberté : on écrit quand on veut, comme on veut. Le Souci de soi comme dirait Foucault, l’espace dominé par les sensations, et la temporalité marquée par la notion d’instants, de moments ayant une connotation expressément personnelle sont autant d’indices révélant la pratique de l’écriture intime en ligne. Le blog appara t à des moments de vie et accompagne souvent des tournants biographiques (ruptures, questionnement mais aussi nouveaux apprentissages, nouvelles rencontres, etc.). Nous proposons dans cet article d’analyser le blog en tant que support de mémoire personnelle et d’étudier à travers des exemples concrets les stratégies développées par les blogueurs pour se créer via ce dispositif communicationnel innovant un espace de conserverie de soi en ligne. Keeping a journal has become a way of live, or to moment a moment in one’s life (Lejeune, 2006). It has multiple uses: construction of a narrative identity, marking time, liberating the self, introspection, self-control, self-support, organization of thoughts or the pleasure of writing. If paper writing is still the most common form of biographical narrative, other media like television or radio have offered new areas of experimentation with these stories of self. More recently, the advent of the Internet and its easy publishing tools have triggered the emergence of innovative biographical forms. Yet, whether to overcome a crisis, keep the memory of a powerful experience, or, more generally, recount his travels and his vacation, the journal is positioned above all as a space of freedom: one writes when one wants to and the way she wants to. The "Care of the Self" as Foucault would s
Holobiont–Holobiont Interactions: Redefining Host–Parasite Interactions
Nolwenn Marie Dheilly
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004093
Modeling synthetic lethality
Nolwenn Le Meur, Robert Gentleman
Genome Biology , 2008, DOI: 10.1186/gb-2008-9-9-r135
Abstract: In Saccharomyces cerevisiae, we identified multi-protein complexes and pairs of multi-protein complexes that share an unusually high number of synthetic genetic interactions. As previously predicted, we found that synthetic lethality can arise from subunits of an essential multi-protein complex or between pairs of multi-protein complexes. Finally, using multi-protein complexes allowed us to take into account the pleiotropic nature of the gene products.Modeling synthetic lethality using current estimates of the yeast interactome is an efficient approach to disentangle some of the complex molecular interactions that drive a cell. Our model in conjunction with applied statistical methods and computational methods provides new tools to better characterize synthetic genetic interactions.Two genes are said to be synthetic lethal if mutation of either alone leaves the cell viable, while simultaneous mutation leads to death. In this case, we say that one gene buffers the effect of changes in the other, that is, compensates for the effect of its deletion. The implications of synthetic lethal screening have already been discussed in the context of anticancer therapies and drug development in general [1,2]. Indeed, synthetic lethal pairs could be used to selectively kill cancer cells, but leave normal cells relatively unharmed. Although several cellular processes might give rise to synthetic lethality, none are yet well understood. Kaelin [1] proposed that synthetic lethality in loss-of-function alleles can arise from at least four different mechanisms (Figure 1). The cellular organizational units might be uniquely redundant and their roles are essential (type A; direct surrogacy), subunits of an essential multi-protein complex (type B), interconnected components in an essential linear pathway (type C), or they might participate in parallel pathways that are together essential (type D).In Saccharomyces cerevisiae, previous analyses of synthetic genetic datasets have mainly rel
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