Institute for Integrative Biology of the Cell

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Summary

Quelles missions pour la recherche face aux crises de l'anthropocène?

What are the missions for research facing energy-climate change crises ?

Lundi 6 février à 11h dans l’Auditorium du bâtiment 21  – Séminaire en français, ouvert à tous – 

Depuis deux siècles, l’utilisation d’une énergie abondante et peu chère permise par les progrès technologiques a progressivement libéré l’homme de sa condition d’agriculteur et conduit à un confort de vie sans équivalent dans l’histoire. Ces changements se sont accompagnés d’une complexification rapide de la société et ont permis notamment l’émergence d’une recherche fonctionnarisée soutenue par des budgets sanctuarisés. Celle-ci, de moins en moins finalisée, nous permet de comprendre le monde qui nous entoure et choisir parmi les futurs possibles. Malheureusement, cette construction sociétale récente vacille car cette énergie abondante, principalement fossile, est en quantité limitée. Par ailleurs, son utilisation déstabilise directement le climat et indirectement nous pousse à dépasser les limites planétaires. Il est évident que le XXIème siècle sera celui de grands changements –subits ou souhaités- car lutter contre le changement climatique veut dire renoncer à une composante majeure de l’abondance actuelle. J’essaierai de montrer que c’est aussi peut être celui de la fin de la recherche telle que nous la pratiquons. Sa forte dépendance à l’énergie la rend particulièrement fragile alors qu’elle est plus que jamais nécessaire pour comprendre l’évolution rapide du monde actuel sous la pression humaine. Mais si, contrainte en moyen et limitée en temps, elle doit disparaître, ne faut-il pas en requestionner les modalités et finalité ? La présentation est largement et librement inspirée des travaux de Jean-Marc Jancovici.

Contact:  Sébastien Thomine <sebastien.thomine@i2bc.paris-saclay.fr >

Monday february the 6th in I2BC Auditorium Bld 21-  Seminar in french, open to all – 

For two centuries, the use of abundant and cheap energy made possible by technological progress has progressively freed man from his condition as a farmer and led to a standard of living without equivalent in history. These changes have been accompanied by a rapid increase in the complexity of society and have led to the emergence of a functional research system supported by dedicated budgets. This research, less and less finalised, allows us to understand the world around us and to choose among possible futures. Unfortunately, this recent societal construction is faltering because this abundant, mainly fossil, energy is in short supply. Moreover, its use directly destabilises the climate and indirectly pushes us to overuse the resources of our planet. It is clear that the 21st century will be one of great changes – whether intentional or unintended – because combating climate change means giving up a major component of the current abundance. I will try to show that it may also be the end of research as we know it. Its heavy dependence on energy makes it particularly fragile, even though it is more necessary than ever to understand the rapid evolution of today’s world under human pressure. Should we reconsider the modalities and purpose of research? The presentation is largely and freely inspired by the work of Jean-Marc Jancovici.

Contact:  Sébastien Thomine <sebastien.thomine@i2bc.paris-saclay.fr >

Properties of rabies virus phosphoprotein and nucleoprotein biocondensates formed in vitro and in cellulo

Rabies virus factories are formed by liquid-liquid phase separation. Nevers et al. have developed and characterized two minimal systems, one cellular, the other acellular, which lead to the formation of condensates having the same properties as the viral factories.

Rabies virus (RABV) is a neurotropic virus causing fatal encephalitis in mammals. RABV transcription and replication take place in viral factories, called Negri bodies (NBs), having liquid properties and formed by liquid-liquid phase separation (LLPS). To decipher the molecular bases underlying such processes, it is necessary to design versatile and easy-to-manipulate minimal systems that recapitulate the characteristics of those viral condensates.
Co-expression of RABV nucleoprotein (N, which tightly binds the viral genome) and phosphoprotein (P, a cofactor of the viral polymerase) in cells is sufficient to induce the formation of condensates with properties similar to NBs. This cellular minimal system was previously used to identify P domains essential for condensate formation. Here, we constructed fluorescent versions of N and analyzed their dynamics inside the condensates using FRAP. N behaves differently from P as there is no fluorescence recovery of N after photobleaching. We also identified 3 arginine residues and two loops of N involved in condensate formation.
We also demonstrated that in vitro, in crowded environments, purified P as well as purified N0-P complex (in which N is RNA-free) form liquid condensates. P domains required for LLPS in this acellular system are the same as those required in the cellular minimal system. P condensates associate with liposomes, concentrate RNA, and undergo a liquid-gel transition upon ageing. Conversely, N0-P condensates are disrupted upon incubation with RNA. Taken together, our data emphasize the role of P in NBs formation and reveal some physicochemical features of P and N0-P condensates relevant for explaining NBs properties such as their envelopment by cellular membranes at late stages of infection and nucleocapsids ejections from the viral factories.
These minimal systems will be useful to characterize weak interactions between proteins involved in NBs formation using biophysical techniques.

More information: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011022

Contact:  Yves Gaudin <yves.gaudin@i2bc.paris-saclay.fr >

Accurate atomic model of the hepatitis E virus replication polyprotein

AlphaFold modelling of the multi-domain replication polyprotein of hepatitis E virus fosters insights on how this emerging pathogen generates new RNA viral genomes in infected cells.

Structural biology, the field that produces atomic-level structures of biomacromolecules, has undergone several revolutions in the last ten years. The latest, and possibly the most far-reaching, is the development of artificial intelligence-based prediction of atomic structures of proteins from their sequence. The program AlphaFold has thus demonstrated an amazing capability to produce atomic models of proteins whose accuracy is actually on a par with that of experimental structures derived from X-ray crystallography or high resolution cryo-electron microscopy. Previously this could be achieved only for proteins with very high sequence identity to a protein of known structure. This development is thus particularly important for RNA viruses, whose sequences diverge fast and the proteins of which consequently never have high sequence similarity to other proteins of known structures.
Using AlphaFold, we modelled the hepatitis E virus (HEV) pORF1, the 1700-residue polyprotein that contains the necessary enzymatic activities to synthesise new HEV genomes in infected cells. We describe a five-domain protein with now clear boundaries for domains. The first of these, previously assigned to two distinct methyltransferase and Y domains, actually contains in a single domain both the activities necessary to cap the new viral RNAs (Met part), and interspersed membrane-interacting elements (Y part). We thus term this N-terminal domain MetY. The atomic structure of MetY is clearly homologous to the Chikungunya virus nsP1, despite very low sequence identity except in the methyltransferase active site. We propose a dodecameric assembly for MetY, as has been described experimentally for nsP1. MetY would thus form a pore allowing translocation from the membrane replication compartment to the cytosol coupled to capping of newly synthesised RNAs.
Most RNA viruses with genomes similar to HEV’s, such as hepatitis C virus (HCV), Chikungunya virus, Zika virus, or SARS-CoV-2, cleave their replication polyproteins into mature proteins with virally-encoded proteases. Our atomic model suggests that for HEV structural flexibility rather than proteolytic processing would serve to regulate pORF1 functions. The case of HCV has shown that direct-acting antivirals could cure chronic RNA virus infection, such as occurs in most HEV infections of immunocompromised patients. This work is a step forward in defining the molecular targets for such future HEV antivirals.

More information: https://www.sciencedirect.com/science/article/pii/S0042682222002136

Contact:  Sonia Fieulaine <sonia.fieulaine@i2bc.paris-saclay.fr> Thibault Tubiana <thibault.tubiana@i2bc.paris-saclay.fr>

How to tell a gene where and when it should be active?

A new study has dissected the complex interactions between regulatory layers that fine-tune the activity of a gene which is essential for the correct formation of the embryo.

The formation of the embryo, from humans to flies, requires a precise orchestration of gene activity: genes need to be turned on at the right time, the right place and at the right level. This regulation of activity incorporates different layers, including the activation of regulatory elements through transcription factor binding, the separation between regulatory regions in the genome through insulator protein binding at boundaries, the epigenetic modifications of large stretches of DNA and the higher-order conformation of chromosomes. How these regulatory layers interact among each other, and particularly how they may instruct each other, remains poorly understood. In this study, PhD student Laura Moniot-Perron in the Chromatin Dynamics group of the I2BC, under the supervision of Daan Noordermeer and Sébastien Bloyer, has studied this question for the Abd-B gene, a prototype gene for embryogenesis. The Abd-B gene encodes a transcription factor that specifies segmental identities along the Antero-Posterior (head-to-tail) body axis. At different positions along this body axis, the gene is activated by different regulatory elements that are located increasingly nearby on the chromosome at more posterior positions. Until now, the question how different regulatory layers are involved in the differential activity along the body axis remained largely unknown. Comparison of cells from different positions along the Antero-Posterior axis revealed the importance of the Fab-7 boundary to create different domains of epigenetic modifications and higher-order chromosome conformation. The resulting cell type-specific organizations differentially activate the different promoters of the Abd-B gene, thereby revealing new possibilities to precisely fine-tune the activity of genes involved in embryogenesis.

More information: https://doi.org/10.1016/j.celrep.2022.111967

Contact: Daan Noordermeer  <daan.noordermeer@i2bc.paris-saclay.fr>

New insights into genome annotation in Podospora anserina through re‑exploiting multiple RNA‑seq data

Thanks to multiple RNA-seq data available on public databases, we were able to improve the genome annotation on Podospora anserina and predict important regulatory features such as UTRs, alternative splicing and new transcription units.

Publicly available RNA-seq datasets are often underused although being helpful to improve functional annotation of eukaryotic genomes. This is especially true for filamentous fungi genomes which structure differs from most well annotated yeast genomes. Podospora anserina is a filamentous fungal model, which genome has been sequenced and annotated in 2008. Still, the current annotation lacks information about cis-regulatory elements, including promoters, transcription starting sites and terminators, which are instrumental to integrate epigenomic features into global gene regulation strategies. Here we took advantage of 37 RNA-seq experiments that were obtained in contrasted developmental and physiological conditions, to complete the functional annotation of P. anserina genome. Out of the 10,800 previously annotated genes, 5’UTR and 3’UTR were defined for 7554, among which, 3328 showed differential transcriptional signal starts and/or transcriptional end sites. In addition, alternative splicing events were detected for 2350 genes, mostly due alternative 3’splice sites and 1732 novel transcriptionally active regions (nTARs) in unannotated regions were identified. Our study provides a comprehensive genome-wide functional annotation of P. anserina genome, including chromatin features, cis-acting elements such as UTRs, alternative splicing events and transcription of noncoding regions. These new findings will likely improve our understanding of gene regulation strategies in compact genomes, such as those of filamentous fungi. Characterization of alternative transcripts and nTARs paves the way to the discovery of putative new genes, alternative peptides or regulatory non-coding RNAs.

More information: https://rdcu.be/c2C2M

Contact: Pierre Grognet <pierre.grognet@i2bc.paris-saclay.fr>

Strategic Axes Day

Program (EV)

9h-9h20 : Introduction (amphitheatre, building 21)

9h20-10h20 : Feedback on programs selected in 2021 (amphitheatre, building 21)

9h20-9h50 MEMlessCOM, axis 1 (F. Frottin, Y. Gaudin)

9h50-10h20 EpiRNA, axis 2 (O. Namy)

10h20-10h50 : Coffee break (hall, building 21)

10h50-11h50 : Feedback on programs selected in 2021, continued (amphi, building 21)

10h50-11h20 Macro, axis 1 (C. Le Clainche, J. Ménétrey, AM Tassin, B. Gigant)

11h20-11h50 AssemblyArt, axis 4 (P. Minard, A. Urvoas)

11h50-12h50 : Feedback on programs selected in 2022 (amphi, building 21)

11h50-12h05 ReMembER, axes 1 & 3 (A. Esclatine, F. Giordano)

12h05-12h20 RecoLiPro, axis 1 (S. Bressanelli, G. Lenoir, T. Touzé)

12h20-12h35 AC/DC, axis 2 (S. Bury-Moné, D. Noordermeer)

12h35-12h50 MnAR, axis 4 (A. Krieger-Liszkay)

13h-14h : Lunch in small groups (canteen)

14h-15h : Parallel thematic workshops (amphi and blue room, building 21 +  rooms N0-001 et N0-009, building 22)

–        Axes/programs, inter-team exchanges and scientific animation

–        Axes/programs, technological developments and platforms/facilities

–        I2BC axes in the Paris-Saclay environment (links with other institutes, GS, OI, EUGLOH…)

–        Scientific themes to be developed (proposals and ideas, within or between axes)

15h-15h30 : Coffee break (hall, building 21)

15h30-17h : : Restitution of the workshops and general discussion (amphitheatre, building 21)

Programme   (VF)

9h-9h20 : Introduction (amphi bât 21)

9h20-10h20 : Retours sur les programmes de la vague 2021 (amphi bât 21)

9h20-9h50 MEMlessCOM, axe 1 (F. Frottin, Y. Gaudin)

9h50-10h20 EpiRNA, axe 2 (O. Namy)

10h20-10h50 : Pause-café (hall bât 21)

10h50-11h50 : Retours sur les programmes de la vague 2021,                                     suite (amphi bât 21)

10h50-11h20 Macro, axe 1 (C. Le Clainche, J. Ménétrey, AM Tassin, B. Gigant)

11h20-11h50 AssemblyArt, axe 4 (P. Minard, A. Urvoas)

11h50-12h50 : Retours sur les programmes de la vague 2022 (amphi bât 21)

11h50-12h05 ReMembER, axes 1 & 3 (A. Esclatine, F. Giordano)

12h05-12h20 RecoliPro, axe 1 (S. Bressanelli, G. Lenoir, T. Touzé)

12h20-12h35 AC/DC, axe 2 (S. Bury-Moné, D. Noordermeer)

12h35-12h50 MnAR, axe 4 (A. Krieger-Liszkay)

13h-14h : Déjeuner libre (cantine par petits groupes)

14h-15h : Ateliers parallèles thématiques (amphi et salle bleue bât 21 + salles N0-001 et N0-009 bât 22)

–  Axes/programmes, échanges inter-équipes et animation scientifique

–  Axes/programmes, développements technologiques et plateformes

–  Axes I2BC dans l’environnement Paris-Saclay (liens avec autres instituts, GS, OI, EUGLOH…)

–  Thématiques scientifiques à développer (propositions et idées, dans un axe ou inter-axes)

15h-15h30 : Pause-café (hall bât 21)

15h30-17h : Restitution des ateliers et discussion générale (amphi bât 21)

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