The Experts below are selected from a list of 10557 Experts worldwide ranked by ideXlab platform
Claudine Chaouiya - One of the best experts on this subject based on the ideXlab platform.
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in silico Logical Modelling to uncover cooperative interactions in cancer
International Journal of Molecular Sciences, 2021Co-Authors: Gianluca Selvaggio, Claudine Chaouiya, Florence JanodyAbstract:The multistep development of cancer involves the cooperation between multiple molecular lesions, as well as complex interactions between cancer cells and the surrounding tumour microenvironment. The search for these synergistic interactions using experimental models made tremendous contributions to our understanding of oncogenesis. Yet, these approaches remain labour-intensive and challenging. To tackle such a hurdle, an integrative, multidisciplinary effort is required. In this article, we highlight the use of Logical computational models, combined with experimental validations, as an effective approach to identify cooperative mechanisms and therapeutic strategies in the context of cancer biology. In silico models overcome limitations of reductionist approaches by capturing tumour complexity and by generating powerful testable hypotheses. We review representative examples of Logical models reported in the literature and their validation. We then provide further analyses of our Logical model of Epithelium to Mesenchymal Transition (EMT), searching for additional cooperative interactions involving inputs from the tumour microenvironment and gain of function mutations in NOTCH.
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EpiLog: A software for the Logical Modelling of epithelial dynamics.
F1000Research, 2018Co-Authors: Pedro L. Varela, Pedro T. Monteiro, Camila V. Ramos, Claudine ChaouiyaAbstract:Cellular responses are governed by regulatory networks subject to external signals from surrounding cells and to other micro-environmental cues. The Logical (Boolean or multi-valued) framework proved well suited to study such processes at the cellular level, by specifying qualitative models of involved signalling pathways and gene regulatory networks. Here, we describe and illustrate the main features of EpiLog, a computational tool that implements an extension of the Logical framework to the tissue level. EpiLog defines a collection of hexagonal cells over a 2D grid, which embodies a mono-layer epithelium. Basically, it defines a cellular automaton in which cell behaviours are driven by associated Logical models subject to external signals. EpiLog is freely available on the web at http://epilog-tool.org . It is implemented in Java (version ≥1.7 required) and the source code is provided at https://github.com/epilog-tool/epilog under a GNU General Public License v3.0.
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Logical Modelling uncovers developmental constraints for primary sex determination of chicken gonads
Journal of the Royal Society Interface, 2018Co-Authors: Lucas Sanchez, Claudine ChaouiyaAbstract:In the chicken, sex determination relies on a ZZ (male)/ZW (female) chromosomal system, but underlying mechanisms are still not fully understood. The Z-dosage and the dominant W-chromosome hypotheses have been proposed to underlie primary sex determination. We present a Modelling approach, which assembles the current knowledge and permits exploration of the regulation of this process in chickens. Relying on published experimental data, we assembled a gene network, which led to a Logical model that integrates both the Z-dosage and dominant W hypotheses. This model showed that the sexual fate of chicken gonads results from the resolution of the mutual inhibition between DMRT1 and FOXL2, where the initial amount of DMRT1 product determines the development of the gonads. In this respect, at the initiation step, a W-factor would function as a secondary device, by reducing the amount of DMRT1 in ZW gonads when the sexual fate of the gonad is settled, that is when the SOX9 functional level is established. Developmental constraints that are instrumental in this resolution were identified. These constraints establish qualitative restrictions regarding the relative transcription rates of the genes DMRT1, FOXL2 and HEMGN. Our model further clarified the role of OESTROGEN in maintaining FOXL2 function during ovary development.
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Logical Modelling and analysis of cellular regulatory networks with ginsim 3 0
bioRxiv, 2018Co-Authors: Aurelien Naldi, Claudine Chaouiya, Pedro T. Monteiro, Celine Hernandez, Wassim Aboujaoude, Denis ThieffryAbstract:The Logical formalism is well adapted to model large cellular networks, for which detailed kinetic data are scarce. This tutorial focuses on this well-established qualitative framework. Relying on GINsim (release 3.0), a software implementing this formalism, we guide the reader step by step towards the definition, the analysis and the simulation of a four-node model of the mammalian p53-Mdm2 network.
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supplementary material from Logical Modelling uncovers developmental constraints for primary sex determination of chicken gonads
2018Co-Authors: Lucas Sanchez, Claudine ChaouiyaAbstract:In chicken, sex determination relies on a ZZ (male)/ZW (female) chromosomal system, but underlying mechanisms are still not fully understood. The Z-dosage and the dominant W-chromosome hypotheses have been proposed to underlie primary sex determination. We present a Modelling approach, which assembles the current knowledge and permits exploring the regulation of this process in chicken. Relying on published experimental data, we assembled a gene network, which led to a Logical model that integrates both the Z-dosage and dominant W hypotheses. This model showed that the sexual fate of chicken gonads results from the resolution of the mutual inhibition between DMRT1 and FOXL2, where the initial amount of DMRT1 product determines the development of the gonads. In this respect, at the initiation step, a W-factor would function as a secondary device, by reducing the amount of DMRT1 in ZW gonads when the sexual fate of the gonad is settled, that is when SOX9 functional level is established. Developmental constraints that are instrumental in this resolution were identified. These constraints establish qualitative restrictions regarding the relative transcription rates of the genes DMRT1, FOXL2 and HEMGN. Our model further clarified the role of OESTROGEN in maintaining FOXL2 function during ovary development.
Denis Thieffry - One of the best experts on this subject based on the ideXlab platform.
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Logical Modelling of in vitro differentiation of human monocytes into dendritic cells unravels novel transcriptional regulatory interactions
Interface Focus, 2021Co-Authors: Karen J Nunezreza, Aurelien Naldi, Denis Thieffry, Arantza Sanchezjimenez, Ana V Leonapodaca, Angelica M Santana, Morgane Thomaschollier, Alejandra MedinariveraAbstract:Dendritic cells (DCs) are the major specialized antigen-presenting cells, thereby connecting innate and adaptive immunity. Because of their role in establishing adaptive immunity, they constitute promising targets for immunotherapy. Monocytes can differentiate into DCs in vitro in the presence of colony-stimulating factor 2 (CSF2) and interleukin 4 (IL4), activating four signalling pathways (MAPK, JAK/STAT, NFKB and PI3K). However, the downstream transcriptional programme responsible for DC differentiation from monocytes (moDCs) remains unknown. By analysing the scientific literature on moDC differentiation, we established a preliminary Logical model that helped us identify missing information regarding the activation of genes responsible for this differentiation, including missing targets for key transcription factors (TFs). Using ChIP-seq and RNA-seq data from the Blueprint consortium, we defined active and inactive promoters, together with differentially expressed genes in monocytes, moDCs and macrophages, which correspond to an alternative cell fate. We then used this functional genomic information to predict novel targets for previously identified TFs. By integrating this information, we refined our model and recapitulated the main established facts regarding moDC differentiation. Prospectively, the resulting model should be useful to develop novel immunotherapies targeting moDCs.
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Logical Modelling and analysis of cellular regulatory networks with ginsim 3 0
bioRxiv, 2018Co-Authors: Aurelien Naldi, Claudine Chaouiya, Pedro T. Monteiro, Celine Hernandez, Wassim Aboujaoude, Denis ThieffryAbstract:The Logical formalism is well adapted to model large cellular networks, for which detailed kinetic data are scarce. This tutorial focuses on this well-established qualitative framework. Relying on GINsim (release 3.0), a software implementing this formalism, we guide the reader step by step towards the definition, the analysis and the simulation of a four-node model of the mammalian p53-Mdm2 network.
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Cooperative development of Logical Modelling standards and tools with CoLoMoTo.
Bioinformatics, 2015Co-Authors: Aurelien Naldi, Denis Thieffry, Pedro T. Monteiro, Christoph Müssel, Tools, Hans A. Kestler, Ioannis Xenarios, Julio Saez-rodriguez, Tomáš Helikar, Claudine ChaouiyaAbstract:The identification of large regulatory and signalling networks involved in the control of crucial cellular processes calls for proper Modelling approaches. Indeed, models can help elucidate properties of these networks, understand their behaviour and provide (testable) predictions by performing in silico experiments. In this context, qualitative, Logical frameworks have emerged as relevant approaches, as demonstrated by a growing number of published models, along with new methodologies and software tools. This productive activity now requires a concerted effort to ensure model reusability and interoperability between tools. Following an outline of the Logical Modelling framework, we present the most important achievements of the Consortium for Logical Models and Tools, along with future objectives. Our aim is to advertise this open community, which welcomes contributions from all researchers interested in Logical Modelling or in related mathematical and computational developments.
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Logical Modelling of Drosophila signalling pathways
Molecular bioSystems, 2013Co-Authors: Abibatou Mbodj, Guillaume Junion, Christine Brun, Eileen E. M. Furlong, Denis ThieffryAbstract:A limited number of signalling pathways are involved in the specification of cell fate during the development of all animals. Several of these pathways were originally identified in Drosophila. To clarify their roles, and possible cross-talk, we have built a Logical model for the nine key signalling pathways recurrently used in metazoan development. In each case, we considered the associated ligands, receptors, signal transducers, modulators, and transcription factors reported in the literature. Implemented using the Logical Modelling software GINsim, the resulting models qualitatively recapitulate the main characteristics of each pathway, in wild type as well as in various mutant situations (e.g. loss-of-function or gain-of-function). These models constitute pluggable modules that can be used to assemble comprehensive models of complex developmental processes. Moreover, these models of Drosophila pathways could serve as scaffolds for more complicated models of orthologous mammalian pathways. Comprehensive model annotations and GINsim files are provided for each of the nine considered pathways.
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Logical Modelling of gene regulatory networks with ginsim
Methods of Molecular Biology, 2012Co-Authors: Claudine Chaouiya, Aurelien Naldi, Denis ThieffryAbstract:Discrete mathematical formalisms are well adapted to model large bioLogical networks, for which detailed kinetic data are scarce. This chapter introduces the reader to a well-established qualitative (Logical) framework for the Modelling of regulatory networks. Relying on GINsim, a software implementing this Logical formalism, we guide the reader step by step towards the definition and the analysis of a simple model of the lysis‐lysogeny decision in the bacteriophage l.
Adrien Faure - One of the best experts on this subject based on the ideXlab platform.
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Logical Modelling of cell cycle control in eukaryotes: a comparative study
Molecular bioSystems, 2009Co-Authors: Adrien Faure, Denis ThieffryAbstract:Dynamical Modelling is at the core of the systems biology paradigm. However, the development of comprehensive quantitative models is complicated by the daunting complexity of regulatory networks controlling crucial bioLogical processes such as cell division, the paucity of currently available quantitative data, as well as the limited reproducibility of large-scale experiments. In this context, qualitative Modelling approaches offer a useful alternative or complementary framework to build and analyse simplified, but still rigorous dynamical models. This point is illustrated here by analysing recent Logical models of the molecular network controlling mitosis in different organisms, from yeasts to mammals. After a short introduction covering cell cycle and Logical Modelling, we compare the assumptions and properties underlying these different models. Next, leaning on their transposition into a common Logical framework, we compare their functional structure in terms of regulatory circuits. Finally, we discuss assets and prospects of qualitative approaches for the Modelling of the cell cycle.
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Modular Logical Modelling of the budding yeast cell cycle
Molecular bioSystems, 2009Co-Authors: Adrien Faure, Aurelien Naldi, Claudine Chaouiya, Fabrice Lopez, Andrea Ciliberto, Denis ThieffryAbstract:Systems biologists are facing the difficult challenge of Modelling and analysing regulatory networks encompassing numerous and diverse components and interactions. Furthermore, available data sets are often qualitative, which complicates the definition of truly quantitative models. In order to build comprehensive and predictive models, there is clearly a need for incremental strategies, enabling the progression from relatively small to large scale models. Leaning on former models, we have defined a Logical model for three regulatory modules involved in the control of the mitotic cell cycle in budding yeast, namely the core cell cycle module, the morphogenetic checkpoint, and a module controlling the exit from mitosis. Consistency with available data has been assessed through a systematic analysis of model behaviours for various genetic backgrounds and other perturbations. Next, we take advantage of compositional facilities of the Logical formalism to combine these three models in order to generate a single comprehensive model involving over thirty regulatory components. The resulting Logical model preserves all relevant characteristics of the original modules, while enabling the simulation of more sophisticated experiments.
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Logical Modelling of regulatory networks with GINsim 2.3
Bio Systems, 2009Co-Authors: Aurelien Naldi, Adrien Faure, Denis Thieffry, Duncan Berenguier, Fabrice Lopez, Claudine ChaouiyaAbstract:Many important problems in cell biology require the consideration of dense nonlinear interactions between functional modules. The requirement of computer simulation for the understanding of cellular processes is now widely accepted, and a variety of Modelling frameworks have been designed to meet this need. Here, we present a novel public release of the Gene Interaction Network simulation suite (GINsim), a software designed for the qualitative Modelling and analysis of regulatory networks. The main functionalities of GINsim are illustrated through the analysis of a Logical model for the core network controlling the fission yeast cell cycle. The last public release of GINsim (version 2.3), as well as development versions, can be downloaded from the dedicated website (http://gin.univ-mrs.fr/GINsim/), which further includes a model library, along with detailed tutorial and user manual.
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Logical Modelling and analysis of the budding yeast cell cycle
BMC Bioinformatics, 2007Co-Authors: Adrien Faure, Claudine Chaouiya, Andrea Ciliberto, Denis ThieffryAbstract:The budding yeast cell cycle core engine has been mod-elled in great detail, most notably by the groups of BelaNovak and John Tyson, using a differential formalism.Several models focusing on different regulatory moduleshave been developed. In this respect, the use of a Logicalformalism facilitates the development of more integratedmodels, through the articulation of control modules tothe core engine. Such integrated models are difficult tobuild with the differential formalism due to the lack ofquantitative data, as well as to numerical instabilitiesinherent to large non linear systems.
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dynamical analysis of a generic boolean model for the control of the mammalian cell cycle
Bioinformatics, 2006Co-Authors: Adrien Faure, Aurelien Naldi, Claudine Chaouiya, Denis ThieffryAbstract:Motivation: To understand the behaviour of complex bioLogical regulatory networks, a proper integration of molecular data into a full-fledge formal dynamical model is ultimately required. As most available data on regulatory interactions are qualitative, Logical Modelling offers an interesting framework to delineate the main dynamical properties of the underlying networks. Results: Transposing a generic model of the core network controlling the mammalian cell cycle into the Logical framework, we compare different strategies to explore its dynamical properties. In particular, we assess the respective advantages and limits of synchronous versus asynchronous updating assumptions to delineate the asymptotical behaviour of regulatory networks. Furthermore, we propose several intermediate strategies to optimize the computation of asymptotical properties depending on available knowledge. Availability: The mammalian cell cycle model is available in a dedicated XML format (GINML) on our website, along with our Logical simulation software GINsim ( ). Higher resolution state transitions graphs are also found on this web site (Model Repository page). Contact: thieffry@ibdm.univ-mrs.fr
Aurelien Naldi - One of the best experts on this subject based on the ideXlab platform.
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Logical Modelling of in vitro differentiation of human monocytes into dendritic cells unravels novel transcriptional regulatory interactions
Interface Focus, 2021Co-Authors: Karen J Nunezreza, Aurelien Naldi, Denis Thieffry, Arantza Sanchezjimenez, Ana V Leonapodaca, Angelica M Santana, Morgane Thomaschollier, Alejandra MedinariveraAbstract:Dendritic cells (DCs) are the major specialized antigen-presenting cells, thereby connecting innate and adaptive immunity. Because of their role in establishing adaptive immunity, they constitute promising targets for immunotherapy. Monocytes can differentiate into DCs in vitro in the presence of colony-stimulating factor 2 (CSF2) and interleukin 4 (IL4), activating four signalling pathways (MAPK, JAK/STAT, NFKB and PI3K). However, the downstream transcriptional programme responsible for DC differentiation from monocytes (moDCs) remains unknown. By analysing the scientific literature on moDC differentiation, we established a preliminary Logical model that helped us identify missing information regarding the activation of genes responsible for this differentiation, including missing targets for key transcription factors (TFs). Using ChIP-seq and RNA-seq data from the Blueprint consortium, we defined active and inactive promoters, together with differentially expressed genes in monocytes, moDCs and macrophages, which correspond to an alternative cell fate. We then used this functional genomic information to predict novel targets for previously identified TFs. By integrating this information, we refined our model and recapitulated the main established facts regarding moDC differentiation. Prospectively, the resulting model should be useful to develop novel immunotherapies targeting moDCs.
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Logical Modelling and analysis of cellular regulatory networks with ginsim 3 0
bioRxiv, 2018Co-Authors: Aurelien Naldi, Claudine Chaouiya, Pedro T. Monteiro, Celine Hernandez, Wassim Aboujaoude, Denis ThieffryAbstract:The Logical formalism is well adapted to model large cellular networks, for which detailed kinetic data are scarce. This tutorial focuses on this well-established qualitative framework. Relying on GINsim (release 3.0), a software implementing this formalism, we guide the reader step by step towards the definition, the analysis and the simulation of a four-node model of the mammalian p53-Mdm2 network.
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Cooperative development of Logical Modelling standards and tools with CoLoMoTo.
Bioinformatics, 2015Co-Authors: Aurelien Naldi, Denis Thieffry, Pedro T. Monteiro, Christoph Müssel, Tools, Hans A. Kestler, Ioannis Xenarios, Julio Saez-rodriguez, Tomáš Helikar, Claudine ChaouiyaAbstract:The identification of large regulatory and signalling networks involved in the control of crucial cellular processes calls for proper Modelling approaches. Indeed, models can help elucidate properties of these networks, understand their behaviour and provide (testable) predictions by performing in silico experiments. In this context, qualitative, Logical frameworks have emerged as relevant approaches, as demonstrated by a growing number of published models, along with new methodologies and software tools. This productive activity now requires a concerted effort to ensure model reusability and interoperability between tools. Following an outline of the Logical Modelling framework, we present the most important achievements of the Consortium for Logical Models and Tools, along with future objectives. Our aim is to advertise this open community, which welcomes contributions from all researchers interested in Logical Modelling or in related mathematical and computational developments.
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Logical Modelling of cellular decision processes with ginsim
JOBIM 2012, 2012Co-Authors: Claudine Chaouiya, Aurelien Naldi, Pedro T. Monteiro, Abibatou Mbodj, Duncan Berenguier, Lionel Spinelli, Luca Grieco, Samuel Collombet, Anna Niarakis, Laurent TichitAbstract:Claudine CHAOUIYA, Aurelien NALDI, Lionel SPINELLI, Pedro MONTEIRO, Duncan BERENGUIER, Luca GRIECO, Abibatou MBODJ, Samuel COLLOMBET, Anna NIARAKIS, Laurent TICHIT, Elisabeth REMY and Denis THIEFFRY1 TAGC (INSERM U1090), Marseille, France Institute Gulbenkian of Science, Oeiras, Portugal chaouiya@igc.gulbenkian.pt University of Lausanne, Switzerland Institut de Mathematiques de Luminy, Marseille, France Universite de la Mediterranee, Marseille, France Institut de Biologie de l'Ecole Normale Superieure, Paris, France thieffry@ens.fr CONTRAINTES, INRIA Paris-Rocquencourt, Le Chesney, France
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Logical Modelling of gene regulatory networks with ginsim
Methods of Molecular Biology, 2012Co-Authors: Claudine Chaouiya, Aurelien Naldi, Denis ThieffryAbstract:Discrete mathematical formalisms are well adapted to model large bioLogical networks, for which detailed kinetic data are scarce. This chapter introduces the reader to a well-established qualitative (Logical) framework for the Modelling of regulatory networks. Relying on GINsim, a software implementing this Logical formalism, we guide the reader step by step towards the definition and the analysis of a simple model of the lysis‐lysogeny decision in the bacteriophage l.
Lucas Sanchez - One of the best experts on this subject based on the ideXlab platform.
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Logical Modelling uncovers developmental constraints for primary sex determination of chicken gonads
Journal of the Royal Society Interface, 2018Co-Authors: Lucas Sanchez, Claudine ChaouiyaAbstract:In the chicken, sex determination relies on a ZZ (male)/ZW (female) chromosomal system, but underlying mechanisms are still not fully understood. The Z-dosage and the dominant W-chromosome hypotheses have been proposed to underlie primary sex determination. We present a Modelling approach, which assembles the current knowledge and permits exploration of the regulation of this process in chickens. Relying on published experimental data, we assembled a gene network, which led to a Logical model that integrates both the Z-dosage and dominant W hypotheses. This model showed that the sexual fate of chicken gonads results from the resolution of the mutual inhibition between DMRT1 and FOXL2, where the initial amount of DMRT1 product determines the development of the gonads. In this respect, at the initiation step, a W-factor would function as a secondary device, by reducing the amount of DMRT1 in ZW gonads when the sexual fate of the gonad is settled, that is when the SOX9 functional level is established. Developmental constraints that are instrumental in this resolution were identified. These constraints establish qualitative restrictions regarding the relative transcription rates of the genes DMRT1, FOXL2 and HEMGN. Our model further clarified the role of OESTROGEN in maintaining FOXL2 function during ovary development.
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supplementary material from Logical Modelling uncovers developmental constraints for primary sex determination of chicken gonads
2018Co-Authors: Lucas Sanchez, Claudine ChaouiyaAbstract:In chicken, sex determination relies on a ZZ (male)/ZW (female) chromosomal system, but underlying mechanisms are still not fully understood. The Z-dosage and the dominant W-chromosome hypotheses have been proposed to underlie primary sex determination. We present a Modelling approach, which assembles the current knowledge and permits exploring the regulation of this process in chicken. Relying on published experimental data, we assembled a gene network, which led to a Logical model that integrates both the Z-dosage and dominant W hypotheses. This model showed that the sexual fate of chicken gonads results from the resolution of the mutual inhibition between DMRT1 and FOXL2, where the initial amount of DMRT1 product determines the development of the gonads. In this respect, at the initiation step, a W-factor would function as a secondary device, by reducing the amount of DMRT1 in ZW gonads when the sexual fate of the gonad is settled, that is when SOX9 functional level is established. Developmental constraints that are instrumental in this resolution were identified. These constraints establish qualitative restrictions regarding the relative transcription rates of the genes DMRT1, FOXL2 and HEMGN. Our model further clarified the role of OESTROGEN in maintaining FOXL2 function during ovary development.
