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Accueil > Départements > Biologie des Génomes > Olivier LESPINET : Bio-Informatique Moléculaire

Publications de l’équipe


  • M. Boudard, D. Barth, J. Bernauer, A. Denise, et J. Cohen, « GARN2: coarse-grained prediction of 3D structure of large RNA molecules by regret minimization », Bioinformatics (Oxford, England), 2017.
    Résumé : Motivation: Predicting the 3D structure of RNA molecules is a key feature towards predicting their functions. Methods which work at atomic or nucleotide level are not suitable for large molecules. In these cases, coarse-grained prediction methods aim to predict a shape which could be refined later by using more precise methods on smaller parts of the molecule. Results: We developed a complete method for sampling 3D RNA structure at a coarse-grained model, taking a secondary structure as input. One of the novelties of our method is that a second step extracts two best possible structures close to the native, from a set of possible structures. Although our method benefits from the first version of GARN, some of the main features on GARN2 are very different. GARN2 is much faster than the previous version and than the well-known methods of the state-of-art. Our experiments show that GARN2 can also provide better structures than the other state-of-the-art methods. Availability and implementations: GARN2 is written in Java. It is freely distributed and available at: . Contacts: , Supplementary information: Supplementary data are available at Bioinformatics online.
    Mots-clés : BIM, DBG.

  • J. - F. Dallery, N. Lapalu, A. Zampounis, S. Pigné, I. Luyten, J. Amselem, A. H. J. Wittenberg, S. Zhou, M. V. de Queiroz, G. P. Robin, A. Auger, M. Hainaut, B. Henrissat, K. - T. Kim, Y. - H. Lee, O. Lespinet, D. C. Schwartz, M. R. Thon, et R. J. O'Connell, « Gapless genome assembly of Colletotrichum higginsianum reveals chromosome structure and association of transposable elements with secondary metabolite gene clusters », BMC genomics, vol. 18, nᵒ 1, p. 667, 2017.
    Résumé : BACKGROUND: The ascomycete fungus Colletotrichum higginsianum causes anthracnose disease of brassica crops and the model plant Arabidopsis thaliana. Previous versions of the genome sequence were highly fragmented, causing errors in the prediction of protein-coding genes and preventing the analysis of repetitive sequences and genome architecture. RESULTS: Here, we re-sequenced the genome using single-molecule real-time (SMRT) sequencing technology and, in combination with optical map data, this provided a gapless assembly of all twelve chromosomes except for the ribosomal DNA repeat cluster on chromosome 7. The more accurate gene annotation made possible by this new assembly revealed a large repertoire of secondary metabolism (SM) key genes (89) and putative biosynthetic pathways (77 SM gene clusters). The two mini-chromosomes differed from the ten core chromosomes in being repeat- and AT-rich and gene-poor but were significantly enriched with genes encoding putative secreted effector proteins. Transposable elements (TEs) were found to occupy 7% of the genome by length. Certain TE families showed a statistically significant association with effector genes and SM cluster genes and were transcriptionally active at particular stages of fungal development. All 24 subtelomeres were found to contain one of three highly-conserved repeat elements which, by providing sites for homologous recombination, were probably instrumental in four segmental duplications. CONCLUSION: The gapless genome of C. higginsianum provides access to repeat-rich regions that were previously poorly assembled, notably the mini-chromosomes and subtelomeres, and allowed prediction of the complete SM gene repertoire. It also provides insights into the potential role of TEs in gene and genome evolution and host adaptation in this asexual pathogen.
    Mots-clés : accessory chromosomes, BIM, Colletotrichum higginsianum, DBG, Fungal genome, optical map, secondary metabolism genes, segmental duplication, SMRT sequencing, subtelomeres, transposable elements.

  • A. Glatigny, P. Gambette, A. Bourand-Plantefol, G. Dujardin, et M. - H. Mucchielli-Giorgi, « Development of an in silico method for the identification of subcomplexes involved in the biogenesis of multiprotein complexes in Saccharomyces cerevisiae », BMC systems biology, vol. 11, nᵒ 1, p. 67, 2017.
    Résumé : BACKGROUND: Large sets of protein-protein interaction data coming either from biological experiments or predictive methods are available and can be combined to construct networks from which information about various cell processes can be extracted. We have developed an in silico approach based on these information to model the biogenesis of multiprotein complexes in the yeast Saccharomyces cerevisiae. RESULTS: Firstly, we have built three protein interaction networks by collecting the protein-protein interactions, which involved the subunits of three complexes, from different databases. The protein-protein interactions come from different kinds of biological experiments or are predicted. We have chosen the elongator and the mediator head complexes that are soluble and exhibit an architecture with subcomplexes that could be functional modules, and the mitochondrial bc 1 complex, which is an integral membrane complex and for which a late assembly subcomplex has been described. Secondly, by applying a clustering strategy to these networks, we were able to identify subcomplexes involved in the biogenesis of the complexes as well as the proteins interacting with each subcomplex. Thirdly, in order to validate our in silico results for the cytochrome bc1 complex we have analysed the physical interactions existing between three subunits by performing immunoprecipitation experiments in several genetic context. CONCLUSIONS: For the two soluble complexes (the elongator and mediator head), our model shows a strong clustering of subunits that belong to a known subcomplex or module. For the membrane bc 1 complex, our approach has suggested new interactions between subunits in the early steps of the assembly pathway that were experimentally confirmed. Scripts can be downloaded from the site: .
    Mots-clés : BIM, BIOCELL, BIOMIT, Complex assembly, DBG, Graph clustering, PPI network, Protein complex, Protein-protein interactions, Subcomplex.

  • A. Thiébaut, T. Delaveau, M. Benchouaia, J. Boeri, M. Garcia, G. Lelandais, et F. Devaux, « The CCAAT-Binding Complex Controls Respiratory Gene Expression and Iron Homeostasis in Candida Glabrata », Scientific Reports, vol. 7, nᵒ 1, p. 3531, 2017.
    Résumé : The CCAAT-binding complex (CBC) is a heterotrimeric transcription factor which is widely conserved in eukaryotes. In the model yeast S. cerevisiae, CBC positively controls the expression of respiratory pathway genes. This role involves interactions with the regulatory subunit Hap4. In many pathogenic fungi, CBC interacts with the HapX regulatory subunit to control iron homeostasis. HapX is a bZIP protein which only shares with Hap4 the Hap4Like domain (Hap4L) required for its interaction with CBC. Here, we show that CBC has a dual role in the pathogenic yeast C. glabrata. It is required, along with Hap4, for the constitutive expression of respiratory genes and it is also essential for the iron stress response, which is mediated by the Yap5 bZIP transcription factor. Interestingly, Yap5 contains a vestigial Hap4L domain. The mutagenesis of this domain severely reduced Yap5 binding to its targets and compromised its interaction with Hap5. Hence, Yap5, like HapX in other species, acts as a CBC regulatory subunit in the regulation of iron stress response. This work reveals new aspects of iron homeostasis in C. glabrata and of the evolution of the role of CBC and Hap4L-bZIP proteins in this process.
    Mots-clés : BIM, DBG.


  • S. Hacquard, B. Kracher, K. Hiruma, P. C. Münch, R. Garrido-Oter, M. R. Thon, A. Weimann, U. Damm, J. - F. Dallery, M. Hainaut, B. Henrissat, O. Lespinet, S. Sacristán, E. V. L. van Themaat, E. Kemen, A. C. McHardy, P. Schulze-Lefert, et R. J. O'Connell, « Erratum: Survival trade-offs in plant roots during colonization by closely related beneficial and pathogenic fungi », Nature Communications, vol. 7, p. 13072, 2016.

  • S. Hacquard, B. Kracher, K. Hiruma, P. C. Münch, R. Garrido-Oter, M. R. Thon, A. Weimann, U. Damm, J. - F. Dallery, M. Hainaut, B. Henrissat, O. Lespinet, S. Sacristán, E. Ver Loren van Themaat, E. Kemen, A. C. McHardy, P. Schulze-Lefert, et R. J. O'Connell, « Survival trade-offs in plant roots during colonization by closely related beneficial and pathogenic fungi », Nature Communications, vol. 7, p. 11362, 2016.
    Résumé : The sessile nature of plants forced them to evolve mechanisms to prioritize their responses to simultaneous stresses, including colonization by microbes or nutrient starvation. Here, we compare the genomes of a beneficial root endophyte, Colletotrichum tofieldiae and its pathogenic relative C. incanum, and examine the transcriptomes of both fungi and their plant host Arabidopsis during phosphate starvation. Although the two species diverged only 8.8 million years ago and have similar gene arsenals, we identify genomic signatures indicative of an evolutionary transition from pathogenic to beneficial lifestyles, including a narrowed repertoire of secreted effector proteins, expanded families of chitin-binding and secondary metabolism-related proteins, and limited activation of pathogenicity-related genes in planta. We show that beneficial responses are prioritized in C. tofieldiae-colonized roots under phosphate-deficient conditions, whereas defense responses are activated under phosphate-sufficient conditions. These immune responses are retained in phosphate-starved roots colonized by pathogenic C. incanum, illustrating the ability of plants to maximize survival in response to conflicting stresses.
    Mots-clés : BIM, DBG.

  • G. Klein, C. Mathé, M. Biola-Clier, S. Devineau, E. Drouineau, E. Hatem, L. Marichal, B. Alonso, J. - C. Gaillard, G. Lagniel, J. Armengaud, M. Carrière, S. Chédin, Y. Boulard, S. Pin, J. - P. Renault, J. - C. Aude, et J. Labarre, « RNA-binding proteins are a major target of silica nanoparticles in cell extracts », Nanotoxicology, vol. 10, nᵒ 10, p. 1555-1564, 2016.
    Résumé : Upon contact with biological fluids, nanoparticles (NPs) are readily coated by cellular compounds, particularly proteins, which are determining factors for the localization and toxicity of NPs in the organism. Here, we improved a methodological approach to identify proteins that adsorb on silica NPs with high affinity. Using large-scale proteomics and mixtures of soluble proteins prepared either from yeast cells or from alveolar human cells, we observed that proteins with large unstructured region(s) are more prone to bind on silica NPs. These disordered regions provide flexibility to proteins, a property that promotes their adsorption. The statistical analyses also pointed to a marked overrepresentation of RNA-binding proteins (RBPs) and of translation initiation factors among the adsorbed proteins. We propose that silica surfaces, which are mainly composed of Si-O(-) and Si-OH groups, mimic ribose-phosphate molecules (rich in -O(-) and -OH) and trap the proteins able to interact with ribose-phosphate containing molecules. Finally, using an in vitro assay, we showed that the sequestration of translation initiation factors by silica NPs results in an inhibition of the in vitro translational activity. This result demonstrates that characterizing the protein corona of various NPs would be a relevant approach to predict their potential toxicological effects.
    Mots-clés : B3S, BIM, DBG, IMAPP, intrinsically disordered protein, PEPS, Protein corona, proteomics, RNA binding protein, silica nanoparticles.

  • Z. Yi, M. Manil-Ségalen, L. Sago, A. Glatigny, V. Redeker, R. Legouis, et M. - H. Mucchielli-Giorgi, « SAFER, an Analysis Method of Quantitative Proteomic Data, Reveals New Interactors of the C. elegans Autophagic Protein LGG-1 », Journal of Proteome Research, vol. 15, nᵒ 5, p. 1515-1523, 2016.
    Résumé : Affinity purifications followed by mass spectrometric analysis are used to identify protein-protein interactions. Because quantitative proteomic data are noisy, it is necessary to develop statistical methods to eliminate false-positives and identify true partners. We present here a novel approach for filtering false interactors, named "SAFER" for mass Spectrometry data Analysis by Filtering of Experimental Replicates, which is based on the reproducibility of the replicates and the fold-change of the protein intensities between bait and control. To identify regulators or targets of autophagy, we characterized the interactors of LGG1, a ubiquitin-like protein involved in autophagosome formation in C. elegans. LGG-1 partners were purified by affinity, analyzed by nanoLC-MS/MS mass spectrometry, and quantified by a label-free proteomic approach based on the mass spectrometric signal intensity of peptide precursor ions. Because the selection of confident interactions depends on the method used for statistical analysis, we compared SAFER with several statistical tests and different scoring algorithms on this set of data. We show that SAFER recovers high-confidence interactors that have been ignored by the other methods and identified new candidates involved in the autophagy process. We further validated our method on a public data set and conclude that SAFER notably improves the identification of protein interactors.
    Mots-clés : atg-8/LC3, Autophagy, BIM, BIOCELL, C. elegans, DBG, label free mass spectrometry, OTOFAG, PF, proteomics, SICAPS, statistical methodology.


  • M. Boudard, J. Bernauer, D. Barth, J. Cohen, et A. Denise, « GARN: Sampling RNA 3D Structure Space with Game Theory and Knowledge-Based Scoring Strategies », PloS One, vol. 10, nᵒ 8, p. e0136444, 2015.
    Résumé : Cellular processes involve large numbers of RNA molecules. The functions of these RNA molecules and their binding to molecular machines are highly dependent on their 3D structures. One of the key challenges in RNA structure prediction and modeling is predicting the spatial arrangement of the various structural elements of RNA. As RNA folding is generally hierarchical, methods involving coarse-grained models hold great promise for this purpose. We present here a novel coarse-grained method for sampling, based on game theory and knowledge-based potentials. This strategy, GARN (Game Algorithm for RNa sampling), is often much faster than previously described techniques and generates large sets of solutions closely resembling the native structure. GARN is thus a suitable starting point for the molecular modeling of large RNAs, particularly those with experimental constraints. GARN is available from:
    Mots-clés : Algorithms, BIM, DBG, Game Theory, Knowledge Bases, Models, Molecular, RNA, RNA Folding.

  • B. Brancotte, B. Yang, G. Blin, S. Cohen-Boulakia, A. Denise, et S. Hamel, « Rank aggregation with ties: experiments and analysis », Proceedings of the VLDB Endowment, vol. 8, nᵒ 11, p. 1202-1213, juill. 2015.

  • S. Ithurbide, E. Bentchikou, G. Coste, B. Bost, P. Servant, et S. Sommer, « Single Strand Annealing Plays a Major Role in RecA-Independent Recombination between Repeated Sequences in the Radioresistant Deinococcus radiodurans Bacterium », PLoS genetics, vol. 11, nᵒ 10, p. e1005636, 2015.
    Résumé : The bacterium Deinococcus radiodurans is one of the most radioresistant organisms known. It is able to reconstruct a functional genome from hundreds of radiation-induced chromosomal fragments. Our work aims to highlight the genes involved in recombination between 438 bp direct repeats separated by intervening sequences of various lengths ranging from 1,479 bp to 10,500 bp to restore a functional tetA gene in the presence or absence of radiation-induced DNA double strand breaks. The frequency of spontaneous deletion events between the chromosomal direct repeats were the same in recA+ and in ΔrecA, ΔrecF, and ΔrecO bacteria, whereas recombination between chromosomal and plasmid DNA was shown to be strictly dependent on the RecA and RecF proteins. The presence of mutations in one of the repeated sequence reduced, in a MutS-dependent manner, the frequency of the deletion events. The distance between the repeats did not influence the frequencies of deletion events in recA+ as well in ΔrecA bacteria. The absence of the UvrD protein stimulated the recombination between the direct repeats whereas the absence of the DdrB protein, previously shown to be involved in DNA double strand break repair through a single strand annealing (SSA) pathway, strongly reduces the frequency of RecA- (and RecO-) independent deletions events. The absence of the DdrB protein also increased the lethal sectoring of cells devoid of RecA or RecO protein. γ-irradiation of recA+ cells increased about 10-fold the frequencies of the deletion events, but at a lesser extend in cells devoid of the DdrB protein. Altogether, our results suggest a major role of single strand annealing in DNA repeat deletion events in bacteria devoid of the RecA protein, and also in recA+ bacteria exposed to ionizing radiation.
    Mots-clés : BIM, DBG, Deinococcus, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, Gamma Rays, Genome, Mutation, Radiation Tolerance, RBA, Rec A Recombinases, Recombination, Genetic.

  • J. - P. Lasserre, A. Dautant, R. S. Aiyar, R. Kucharczyk, A. Glatigny, D. Tribouillard-Tanvier, J. Rytka, M. Blondel, N. Skoczen, P. Reynier, L. Pitayu, A. Rotig, A. Delahodde, L. M. Steinmetz, G. Dujardin, V. Procaccio, et J. - P. di Rago, « Yeast as a system for modeling mitochondrial disease mechanisms and discovering therapies », Disease Models & Mechanisms, vol. 8, nᵒ 6, p. 509-526, juin 2015.
    Mots-clés : Animals, BIM, BIOCELL, BIOMIT, DBG, DNA, Fungal, Drug screening, FDMITO, Genetic suppressors, Humans, Mitochondria, Mitochondrial disease, Mitochondrial Diseases, Models, Biological, OXPHOS, Saccharomyces cerevisiae, Translational Medical Research, Yeast.
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Publications Principales avant 2015

-  Bost B, Veitia R (2014). Dominance and interloci interactions in transcriptional activation cascades : A model explaining compensatory mutations and inheritance patterns. BioEssays 36(1) : 84–92.

-  Darty K, Denise A and Ponty Y (2009). VARNA : Interactive drawing and editing of the RNA secondary structure. Bioinformatics 25(15):1974-1975.

-  Dufresne M, Lespinet O, Daboussi MJ, Hua-Van A (2011) Genome-Wide Comparative Analysis of pogo-Like Transposable Elements in Different Fusarium Species. Journal of Molecular Evolution 73 : 230-243.

-  Espagne E, Lespinet O, Malagnac F, Da Silva C, Jaillon O, Porcel BM, Couloux A, Aury JM, Ségurens B, Poulain J, Anthouard V, Grossetete S, Khalili H, Coppin E, Déquard-Chablat M, Picard M, Contamine V, Arnaise S, Bourdais A, Berteaux-Lecellier V, Gautheret D, de Vries RP, Battaglia E, Coutinho PM, Danchin EG, Henrissat B, Khoury RE, Sainsard-Chanet A, Boivin A, Pinan-Lucarré B, Sellem CH, Debuchy R, Wincker P, Weissenbach J, Silar P. (2008) The genome sequence of the model ascomycete fungus Podospora anserina. Genome Biol. 9(5):R77.

-  Glatigny A, Mathieu L, Herbert CJ, Dujardin J, Meunier B, Mucchielli-Giorgi MH (2011) An in silico approach combined with in vivo experiments enables the identification of a new protein controlling the biogenesis of respiratory complexes in Saccharomyces cerevisiae. BMC System Biology, 5 : 173-185.

-  Grossetête S, Labedan B, Lespinet O. (2010) FUNGIpath : a tool to assess fungal metabolic pathways predicted by orthology. BMC Genomics,11:81.

-  Lamiable A, Quessette F, Vial S, Barth D, Denise A, (2012), An algorithmic game-theory approach for coarse-grain prediction of RNA 3D structure, IEEE/ACM Transactions on Computational Biology and Bioinformatics, 10(1) : 193-199.

-  Lopes A, Sacquin-Mora S, Dimitrova V, Laine E, Ponty Y, Carbone A (2013). Protein-protein interactions in a crowded environment : an analysis via cross-docking simulations and evolutionary information. PLoS Comput Biol. 9(12):e1003369

-  Lopes A, Tavares P, Petit MA, Guérois R, Zinn-Justin S (2014). Automated classification of tailed bacteriophages according to their neck organization. BMC Genomics, in press.

-  Pereira C, Denise A, Lespinet O (2014). A meta-approach for improving the prediction and the functional annotation of ortholog groups. BMC Genomics

-  Mathé C, Devineau S, Aude J-C, Lagniel G, Chédin S, Legros V, Mathon M-H, Renault J-P, Pin S, Boulard Y, Labarre J : Structural determinants for protein adsorption/non-adsorption to silica surface. PLoS ONE 2013, 8:e81346.

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