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Accueil > Départements > Biologie des Génomes > Julie SOUTOURINA : Régulation transcriptionnelle des génomes

Publications de l’équipe


  • S. Calderari, M. Ria, C. Gérard, T. C. Nogueira, O. Villate, S. C. Collins, H. Neil, N. Gervasi, C. Hue, N. Suarez-Zamorano, C. Prado, M. Cnop, M. - T. Bihoreau, P. J. Kaisaki, J. - B. Cazier, C. Julier, M. Lathrop, M. Werner, D. L. Eizirik, et D. Gauguier, « Molecular genetics of the transcription factor GLIS3 identifies its dual function in beta cells and neurons », Genomics, 2017.
    Résumé : The GLIS family zinc finger 3 isoform (GLIS3) is a risk gene for Type 1 and Type 2 diabetes, glaucoma and Alzheimer's disease endophenotype. We identified GLIS3 binding sites in insulin secreting cells (INS1) (FDR q<0.05; enrichment range 1.40-9.11 fold) sharing the motif wrGTTCCCArTAGs, which were enriched in genes involved in neuronal function and autophagy and in risk genes for metabolic and neuro-behavioural diseases. We confirmed experimentally Glis3-mediated regulation of the expression of genes involved in autophagy and neuron function in INS1 and neuronal PC12 cells. Naturally-occurring coding polymorphisms in Glis3 in the Goto-Kakizaki rat model of type 2 diabetes were associated with increased insulin production in vitro and in vivo, suggestive alteration of autophagy in PC12 and INS1 and abnormal neurogenesis in hippocampus neurons. Our results support biological pleiotropy of GLIS3 in pathologies affecting β-cells and neurons and underline the existence of trans‑nosology pathways in diabetes and its co-morbidities.
    Mots-clés : Alzheimer's disease, ChIP sequencing, DBG, Diabetes mellitus, Goto-Kakizaki rat, GTR, Quantitative trait locus, Single nucleotide polymorphism.

  • T. Eychenne, M. Werner, et J. Soutourina, « Toward understanding of the mechanisms of Mediator function in vivo: Focus on the preinitiation complex assembly », Transcription, p. e1329000, 2017.
    Résumé : Mediator is a multisubunit complex conserved in eukaryotes that plays an essential coregulator role in RNA polymerase (Pol) II transcription. Despite intensive studies of the Mediator complex, the molecular mechanisms of its function in vivo remain to be fully defined. In this review, we will discuss the different aspects of Mediator function starting with its interactions with specific transcription factors, its recruitment to chromatin and how, as a coregulator, it contributes to the assembly of transcription machinery components within the preinitiation complex (PIC) in vivo and beyond the PIC formation.
    Mots-clés : coactivator, DBG, eukaryotic transcription, functional genomics, Genetics, GTR, human, Mediator, preinitiation complex, RNA Polymerase II, Structural Biology, yeast Saccharomyces cerevisiae.


  • M. de Dieuleveult, K. Yen, I. Hmitou, A. Depaux, F. Boussouar, D. Bou Dargham, S. Jounier, H. Humbertclaude, F. Ribierre, C. Baulard, N. P. Farrell, B. Park, C. Keime, L. Carrière, S. Berlivet, M. Gut, I. Gut, M. Werner, J. - F. Deleuze, R. Olaso, J. - C. Aude, S. Chantalat, B. F. Pugh, et M. Gérard, « Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells », Nature, vol. 530, nᵒ 7588, p. 113-116, 2016.
    Résumé : ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers target specific nucleosomes to regulate transcription is unclear. Here we present genome-wide remodeller-nucleosome interaction profiles for the chromatin remodellers Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank micrococcal nuclease (MNase)-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription. Surprisingly, large CpG-rich NFRs that extend downstream of annotated transcriptional start sites are nevertheless bound by non-nucleosomal or subnucleosomal histone variants (H3.3 and H2A.Z) and marked by H3K4me3 and H3K27ac modifications. RNA polymerase II therefore navigates hundreds of base pairs of altered chromatin in the sense direction before encountering an MNase-resistant nucleosome at the 3' end of the NFR. Transcriptome analysis after remodeller depletion reveals reciprocal mechanisms of transcriptional regulation by remodellers. Whereas at active genes individual remodellers have either positive or negative roles via altering nucleosome stability, at polycomb-enriched bivalent genes the same remodellers act in an opposite manner. These findings indicate that remodellers target specific nucleosomes at the edge of NFRs, where they regulate ES cell transcriptional programs.
    Mots-clés : Animals, Chromatin Assembly and Disassembly, DBG, DNA Helicases, DNA-Binding Proteins, Gene Expression Regulation, Genome, GTR, Histones, Mice, Micrococcal Nuclease, Mouse Embryonic Stem Cells, Nuclear Proteins, Nucleosomes, Promoter Regions, Genetic, REMOD, RNA Polymerase II, Substrate Specificity, Trans-Activators, Transcription Factors, Transcription Initiation Site.

  • T. Eychenne, E. Novikova, M. - B. Barrault, O. Alibert, C. Boschiero, N. Peixeiro, D. Cornu, V. Redeker, L. Kuras, P. Nicolas, M. Werner, et J. Soutourina, « Functional interplay between Mediator and TFIIB in preinitiation complex assembly in relation to promoter architecture », Genes & Development, vol. 30, nᵒ 18, p. 2119-2132, 2016.
    Résumé : Mediator is a large coregulator complex conserved from yeast to humans and involved in many human diseases, including cancers. Together with general transcription factors, it stimulates preinitiation complex (PIC) formation and activates RNA polymerase II (Pol II) transcription. In this study, we analyzed how Mediator acts in PIC assembly using in vivo, in vitro, and in silico approaches. We revealed an essential function of the Mediator middle module exerted through its Med10 subunit, implicating a key interaction between Mediator and TFIIB. We showed that this Mediator-TFIIB link has a global role on PIC assembly genome-wide. Moreover, the amplitude of Mediator's effect on PIC formation is gene-dependent and is related to the promoter architecture in terms of TATA elements, nucleosome occupancy, and dynamics. This study thus provides mechanistic insights into the coordinated function of Mediator and TFIIB in PIC assembly in different chromatin contexts.
    Mots-clés : DBG, GTR, Mediator, PEPS, PF, preinitiation complex, promoter architecture, RNA polymerase II transcription, Saccharomyces cerevisiae, SICAPS, TFIIB.

  • A. Goldar, A. Arneodo, B. Audit, F. Argoul, A. Rappailles, G. Guilbaud, N. Petryk, M. Kahli, et O. Hyrien, « Deciphering DNA replication dynamics in eukaryotic cell populations in relation with their averaged chromatin conformations », Scientific Reports, vol. 6, p. 22469, 2016.
    Résumé : We propose a non-local model of DNA replication that takes into account the observed uncertainty on the position and time of replication initiation in eukaryote cell populations. By picturing replication initiation as a two-state system and considering all possible transition configurations, and by taking into account the chromatin's fractal dimension, we derive an analytical expression for the rate of replication initiation. This model predicts with no free parameter the temporal profiles of initiation rate, replication fork density and fraction of replicated DNA, in quantitative agreement with corresponding experimental data from both S. cerevisiae and human cells and provides a quantitative estimate of initiation site redundancy. This study shows that, to a large extent, the program that regulates the dynamics of eukaryotic DNA replication is a collective phenomenon that emerges from the stochastic nature of replication origins initiation.
    Mots-clés : Cell Line, Chromatin, DBG, DNA Replication, GTR, Humans, Replication Origin, Saccharomyces cerevisiae.


  • A. Bridier-Nahmias, A. Tchalikian-Cosson, J. A. Baller, R. Menouni, H. Fayol, A. Flores, A. Saïb, M. Werner, D. F. Voytas, et P. Lesage, « Retrotransposons. An RNA polymerase III subunit determines sites of retrotransposon integration », Science (New York, N.Y.), vol. 348, nᵒ 6234, p. 585-588, 2015.
    Résumé : Mobile genetic elements are ubiquitous. Their integration site influences genome stability and gene expression. The Ty1 retrotransposon of the yeast Saccharomyces cerevisiae integrates upstream of RNA polymerase III (Pol III)-transcribed genes, yet the primary determinant of target specificity has remained elusive. Here we describe an interaction between Ty1 integrase and the AC40 subunit of Pol III and demonstrate that AC40 is the predominant determinant targeting Ty1 integration upstream of Pol III-transcribed genes. Lack of an integrase-AC40 interaction dramatically alters target site choice, leading to a redistribution of Ty1 insertions in the genome, mainly to chromosome ends. The mechanism of target specificity allows Ty1 to proliferate and yet minimizes genetic damage to its host.
    Mots-clés : Chromosomes, Fungal, DBG, DNA-Directed RNA Polymerases, GTR, Integrases, Retroelements, RNA Polymerase III, RNA, Transfer, Saccharomyces cerevisiae, Schizosaccharomyces pombe Proteins, Transcription, Genetic.

  • F. Eyboulet, S. Wydau-Dematteis, T. Eychenne, O. Alibert, H. Neil, C. Boschiero, M. - C. Nevers, H. Volland, D. Cornu, V. Redeker, M. Werner, et J. Soutourina, « Mediator independently orchestrates multiple steps of preinitiation complex assembly in vivo », Nucleic Acids Research, vol. 43, nᵒ 19, p. 9214-9231, 2015.
    Résumé : Mediator is a large multiprotein complex conserved in all eukaryotes, which has a crucial coregulator function in transcription by RNA polymerase II (Pol II). However, the molecular mechanisms of its action in vivo remain to be understood. Med17 is an essential and central component of the Mediator head module. In this work, we utilised our large collection of conditional temperature-sensitive med17 mutants to investigate Mediator's role in coordinating preinitiation complex (PIC) formation in vivo at the genome level after a transfer to a non-permissive temperature for 45 minutes. The effect of a yeast mutation proposed to be equivalent to the human Med17-L371P responsible for infantile cerebral atrophy was also analyzed. The ChIP-seq results demonstrate that med17 mutations differentially affected the global presence of several PIC components including Mediator, TBP, TFIIH modules and Pol II. Our data show that Mediator stabilizes TFIIK kinase and TFIIH core modules independently, suggesting that the recruitment or the stability of TFIIH modules is regulated independently on yeast genome. We demonstrate that Mediator selectively contributes to TBP recruitment or stabilization to chromatin. This study provides an extensive genome-wide view of Mediator's role in PIC formation, suggesting that Mediator coordinates multiple steps of a PIC assembly pathway.
    Mots-clés : Chromatin, DBG, Galactokinase, Gene Expression Regulation, Fungal, Genome, Fungal, GTR, Mediator Complex, Mutation, PF, RNA Polymerase II, RNA, Messenger, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, SICAPS, TATA-Box Binding Protein, Transcription Factor TFIIH, Transcription Initiation, Genetic.

  • M. Platel, A. Goldar, J. M. Wiggins, P. Barbosa, P. Libeau, P. Priam, H. Narassimprakash, X. Grodzenski, et K. Marheineke, « Tight Chk1 Levels Control Replication Cluster Activation in Xenopus », PloS One, vol. 10, nᵒ 6, p. e0129090, 2015.
    Résumé : DNA replication in higher eukaryotes initiates at thousands of origins according to a spatio-temporal program. The ATR/Chk1 dependent replication checkpoint inhibits the activation of later firing origins. In the Xenopus in vitro system initiations are not sequence dependent and 2-5 origins are grouped in clusters that fire at different times despite a very short S phase. We have shown that the temporal program is stochastic at the level of single origins and replication clusters. It is unclear how the replication checkpoint inhibits late origins but permits origin activation in early clusters. Here, we analyze the role of Chk1 in the replication program in sperm nuclei replicating in Xenopus egg extracts by a combination of experimental and modelling approaches. After Chk1 inhibition or immunodepletion, we observed an increase of the replication extent and fork density in the presence or absence of external stress. However, overexpression of Chk1 in the absence of external replication stress inhibited DNA replication by decreasing fork densities due to lower Cdk2 kinase activity. Thus, Chk1 levels need to be tightly controlled in order to properly regulate the replication program even during normal S phase. DNA combing experiments showed that Chk1 inhibits origins outside, but not inside, already active clusters. Numerical simulations of initiation frequencies in the absence and presence of Chk1 activity are consistent with a global inhibition of origins by Chk1 at the level of clusters but need to be combined with a local repression of Chk1 action close to activated origins to fit our data.
    Mots-clés : Animals, Checkpoint Kinase 1, Computer Simulation, DBG, DNA Replication, DYNREP, Female, GTR, Male, Models, Biological, Ovum, Protein Kinases, Replication Origin, S Phase, Spermatozoa, Up-Regulation, Xenopus, Xenopus Proteins.
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Publications Principales avant 2015

- Pinskaya M., Ghavi-Helm Y., Mariotte-Labarre S., Morillon A., Soutourina J., Werner M. (2014) PHD and TFIIS-like domains of the Bye1 transcription factor determine its multivalent genomic distribution. PLoS One 9(7):e102464.

- Rintisch C., Heinig M., Bauerfeind A., Schafer S., Mieth C., Patone G., Hummel O., Chen W., Cook S., Cuppen E., Colomé-Tatché M., Johannes F., Jansen R. C., Neil H., Werner M., Pravenec M., Vingron M., Hubner N. (2014) Natural variation of histone modification and its impact on gene expression in the rat genome. Genome Res. 24, 942-953.

- Soutourina J. & Werner M. (2014) A novel link of Mediator with DNA repair. Cell Cycle 13, 1362-1363.

- Eyboulet F., Cibot C., Eychenne T., Neil H., Alibert O., Werner M., & Soutourina J. (2013) Mediator links transcription and DNA repair by facilitating Rad2/XPG recruitment. Genes & Dev. 27, 2549-2562.

- Carrière, L., Graziani, S., Alibert, O., Ghavi-Helm, Y., Boussouar, F., Humbertclaude, H., Jounier, S., Aude, J.-C., Keime, C., Murvai, J., Foglio, M., Gut, M., Gut, I., Lathrop, M., Soutourina, J., Gérard, M. and Werner, M. (2012) Genomic binding of Pol III transcription machinery and relationship with TFIIS transcription factor distribution in mouse embryonic stem cells. Nucl. Acids Res. 40, 270-283.

- Werner, M., Toussaint, A. and Mergeay, M. (2012) Pierre Thuriaux (1944-2012). Res. Mic. 163, 398.

- Beckouët F, Mariotte-Labarre S, Peyroche G, Nogi Y, Thuriaux P. (2011). Rpa43 and its partners in the yeast RNA polymerase I transcription complex. FEBS Lett, 585, 3355-3359.

- Carrière L, Graziani S, Alibert O, Ghavi-Helm Y, Boussouar F, Humbertclaude H, Jounier S, Aude J C, Keime C, Murvai J, Foglio M, Gut M, Gut I, Lathrop M, Soutourina J, Gérard M, Werner M. (2011). Genomic binding of Pol III transcription machinery and relationship with TFIIS transcription factor distribution in mouse embryonic stem cells. Nucleic Acids Res. 40, 270-283.

- Garcia-Lopez M C, Pelechano V, Miron-Garcia M C, Garrido-Godino A I, Garcia A, Calvo O, Werner M, Perez-Ortin J E, Navarro F. (2011). The Conserved Foot Domain of RNA Pol II Associates with Proteins Involved in Transcriptional Initiation and/or Early Elongation. Genetics. 189, 1235-1248.

- Soutourina J, Wydau S, Ambroise Y, Boschiero C, Werner M. (2011). Direct Interaction of RNA Polymerase II and Mediator Required for Transcription in Vivo. Science. 331, 1451-1454.

- Werner M. (2011). Transcription and its regulation in eucaryotes. Biofutur. 35-37.
Coudreuse D, van Bakel H, Dewez M, Soutourina J, Parnell T, Vandenhaute J, Cairns B, Werner M, Hermand D. (2010). A gene-specific requirement of RNA polymerase II CTD phosphorylation for sexual differentiation in S. pombe. Curr. Biol., 20, 1053-1064.

- Werner M, Thuriaux P, Soutourina J. (2009). Structure-function analysis of RNA polymerases I and III. Curr. Opin. Struc. Biol., 19, 740-745.

- Beckouet F, Labarre-Mariotte S, Albert B, Imazawa Y, Werner M, Gadal O, Nogi Y, Thuriaux P. (2008). Two RNA Polymerase I Subunits Control the Binding and Release of Rrn3 during Transcription. Mol Cell Biol. 28, 1596-605.

- Esnault C, Ghavi-Helm Y, Brun S, Soutourina J, Van Berkum N, Boschiero C, Holstege F, Werner M. (2008). Mediator-dependent recruitment of TFIIH modules in preinitiation complex. Mol Cell.31, 337 - 346.

- Ghavi-Helm Y, Michaut M, Acker J, Aude JC, Thuriaux T, Werner M, Soutourina J.(2008). Genome-wide location analysis reveals a role of TFIIS in RNA polymerase III transcription. Genes & Dev. 22, 1934-47.

- Kwapisz M, Wery M, Després D, Ghavi-Helm Y, Soutourina J, Thuriaux P, Lacroute F. (2008). Mutations of RNA polymerase II activate key genes of the nucleoside triphosphate biosynthetic pathways. EMBO J. 27, 2411-21.

- Guglielmi B, Soutourina J, Esnault C, Werner M. (2007). TFIIS elongation factor and Mediator act in conjunction during transcription initiation in vivo. Proc Natl Acad Sci U S A. 104, 16062-7.

- Guiguen A, Soutourina J, Dewez M, Tafforeau L, Dieu M, Raes M, Vandenhaute J, Werner M, Hermand D. (2007). Recruitment of P-TEFb (Cdk9-Pch1) to chromatin by the cap-methyl transferase Pcm1 in fission yeast. EMBO J. 26, 1552-1559.

- Loncle N, Boube M, Joulia L, Boschiero C, Werner M, Cribbs DL, Bourbon HM. (2007). Distinct roles for Mediator Cdk8 module subunits in Drosophila development. EMBO J. 26, 1045-1054.

- Zaros C, Briand JF, Boulard Y, Labarre-Mariotte S, Garcia-Lopez MC, Thuriaux P, Navarro F. (2007). Functional organization of the Rpb5 subunit shared by the three yeast RNA polymerases. Nucleic Acids Res. 35, 634-647.

- Soutourina J, Bordas-Le Floch V, Gendrel G, Flores A, Ducrot C, Dumay-Odelot H, Soularue P, Navarro F, Cairns BR, Lefebvre O, Werner M. (2006). Rsc4 Connects the Chromatin Remodeler RSC to RNA Polymerases. Mol Cell Biol. 26, 4920-4930.

- Guffanti E, Percudani R, Harismendy O, Soutourina J, Werner M, Lacovella G, Negri R, Dieci G. (2006). Nucleosome depletion activates poised RNA polymerase III at unconventional transcription sites in Saccharomyces cerevisiae. J Biol Chem. 281, 29155-29164.

- Andrau JC, van de Pasch L, Lijnzaad P, Bijma T, Koerkamp MG, van de Peppel J, Werner M, Holstege FC. (2006). Genome-wide location of the coactivator mediator : Binding without activation and transient Cdk8 interaction on DNA. Mol Cell. 22, 179-192.

- Torchet C, Badis G, Devaux F, Costanzo G, Werner M, Jacquier A. (2005). The complete set of H/ACA snoRNAs that guide rRNA pseudouridylations in Saccharomyces cerevisiae RNA. 11, 928-938.

- Lenssen E, James N, Pedruzzi I, Dubouloz F, Cameroni E, Bisig R, Maillet L, Werner M, Roosen J, Petrovic K, Winderickx J, Collart MA, De Virgilio C. (2005). The Ccr4-Not complex independently controls both Msn2-dependent transcriptional activation—via a newly identified Glc7/Bud14 type i protein phosphatase module—and TFIID promoter distribution. Mol Cell Biol. 25, 488-498.

- Kabani M, Michot K, Boschiero C, Werner M. (2005). Anc1 interacts with the catalytic subunits of the general transcription factors TFIID and TFIIF, the chromatin remodeling complexes RSC and INO80, and the histone acetyltransferase complex NuA3. Biochem Biophys Res Commun. 332, 398-403.

- Schawalder SB, Kabani M, Howald I, Choudhury U, Werner M, Shore D. (2004). Growth-regulated recruitment of the essential yeast ribosomal protein gene activator Ifh1. Nature. 432, 1058-1061.

- Kasten M, Szerlong H, Erdjument-Bromage H, Tempst P, Werner M, Cairns BR. (2004). Tandem bromodomains in the chromatin remodeler RSC recognize acetylated histone H3 Lys14. EMBO J. 23, 1348-1359.

- Guglielmi B, van Berkum NL, Klapholz B, Bijma T, Boube M, Boschiero C, Bourbon HM, Holstege FC, Werner M. (2004). A high resolution protein interaction map of the yeast Mediator complex. Nucleic Acids Res. 32, 5379-5391.

- Guglielmi B, Zaros C, Thuriaux P and Werner M. (2004). Investigating protein-protein interactions in multi-subunit proteins : the case of eukaryotic RNA polymerases. Genetics, Genomics, Proteomics and Bioinformatics Online.

- Siaut M, Zaros C, Levivier E, Ferri ML, Court M, Werner M, Callebaut I, Thuriaux P, Sentenac A, Conesa C. (2003). An Rpb4/Rpb7-like complex in yeast RNA polymerase III contains the orthologue of mammalian CGRP-RCP. Mol Cell Biol. 23, 195-205.

- Harismendy O, Gendrel CG, Soularue P, Gidrol X, Sentenac A, Werner M, Lefebvre O. (2003). Genome-wide location of yeast RNA polymerase III transcription machinery. EMBO J. 22, 4738-4747.

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