Régulation des ARNm et Développement

  • Gene regulation at the post-transcriptional level is of crucial importance in a wide number of biological processes. The main focus of our lab is to understand mRNA regulation in developmental and pathological processes. We are using the Drosophila model, an outstanding model for in vivo studies.

    We have recently identified the role of a specific class of small non-coding RNAs, called Piwi-interacting RNAs (piRNAs) in the regulation of maternal mRNAs during early embryogenesis. piRNAs have been discovered in the last decade in germ cells of animal species. They are loaded into specific Argonaute proteins, the PIWI proteins and their main function is to repress transposable elements in the germline. piRNAs are mostly produced from transposable element sequences. In the last years, we pioneered the discovery of a new function of piRNAs and PIWI proteins in gene regulation. Specifically, piRNAs produced from transposable elements target and repress maternal mRNAs that encode proteins essential for embryonic patterning. These data allowed us to propose the new concept of gene regulation by piRNAs. Furthermore, we revealed a developmental function of transposable elements, a component of the genome whose function has not been clarified. Further studies in other organisms have demonstrated the evolutionary conservation of piRNA function in cellular mRNA regulation. Thus, gene regulation by piRNAs should have a major impact in many biological processes, including diseases.

    Fig1Figure : Scheme of the molecular mechanisms of maternal mRNA regulation by piRNAs and the PIWI protein Aubergine, in the Drosophila embryo (Barckmann et al. Cell Reports 2015; Dufourt et al. Nature Communications 2017).


    Our projects aim at understanding the molecular mechanisms of gene regulation by the piRNA pathway during developmental processes: embryonic development; germline development; stem cell biology; as well as in pathologies.
    We have started the series of biennial EMBO Workshops on piRNAs and PIWI proteins in Montpellier (http://events.embo.org/16-piRNA/; http://meetings.embo.org/event/18-pirna).

    With the aim of deciphering the importance of mRNA regulation in a pathological context, we have  developed a Drosophila model of oculopharyngeal muscular dystrophy (OPMD), a rare genetic disease due to mutations in Poly(A) binding protein nuclear I (PABPN1). PABPN1 has essential functions in nuclear polyadenylation and alternative poly(A) site choice (APA). OPMD results from short alanine expansions at the N terminus of PABPN1. It is characterized by the progressive weakening of specific muscles. Alanine expanded PABPN1 forms nuclear aggregates. OPMD is therefore a proteinopathy, as are Alzheimer and Huntington diseases. Our Drosophila model reproduces the characteristics of the disease. We are using this model to understand the molecular mechanisms underlying disease progression and to identify potential therapies.

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    A ce jour, notre recherche est financée par :

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    Membres

    Patricia Rojas Rios
    Rojas Rios Patricia
    Martine Simonelig
    Simonelig Martine
    Aymeric Chartier
    Chartier Aymeric
    Julie Cremaschi
    Cremaschi Julie
    Celine Garret
    Garret Celine
    Rima Nait-saidi
    Nait-saidi Rima
    Anne Ramat
    Ramat Anne
    Aikaterini Stefanaki
    Stefanaki Aikaterini

    Publications

    The PIWI protein Aubergine recruits eIF3 to activate translation in the germ plasm.

    Ramat A, Garcia-Silva MR, Jahan C, Naït-Saïdi R, Dufourt J, Garret C, Chartier A...

    2020 - Cell Research (2020)., 10.1038/s41422-020-0294-9

    Demander l'article complet

    piRNAs and Aubergine cooperate with Wispy poly(A) polymerase to stabilize mRNAs in the germ plasm

    Dufourt J, Bontonou G, Chartier A, Jahan C, Meunier AC, Pierson S, Harrison PF, Papin C, Beilharz TH, Simonelig M

    2017 - Nat Commun, 8(1):1305

    Demander l'article complet29101389

    Aubergine and piRNAs promote germline stem cell self-renewal by repressing the proto-oncogene Cbl.

    Rojas-Ríos P, Chartier A, Pierson S, Simonelig M

    2017 - EMBO J., 36, 21, 3194-3211

    Demander l'article complet29030484

    Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy.

    Malerba A, Roth F, Harish P, Dhiab J, Lu-Nguyen N, Cappellari O, Jarmin S, Mahoudeau A, Ythier V, Lainé J, Negroni E, Abgueguen E, Simonelig M, Guedat P, Mouly V, Butler-Browne G, Voisset C, Dickson G, Trollet C

    2019 - Hum Mol Genet

    Demander l'article complet30649389
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    Publications de l'équipe

  • To analyze the molecular mechanisms of mRNA regulation by piRNAs and PIWI proteins

    We have shown that the PIWI protein Aubergine (Aub) plays a role in the stability of maternal mRNAs in the embryo: it is involved in both the decay of maternal mRNAs in the somatic part of the embryo, and the stabilization of the same mRNAs in the germ plasm -a specialized cytoplasm at the posterior pole of the embryo, from which the germline develops-.
    Recently, we have identified a new function of Aub in the translational control of maternal mRNAs. We are analyzing this new function.
    mRNA modification or “epitranscriptomics” has emerged has a new layer of gene regulation. We are addressing a potential interplay between piRNAs and epitranscriptomics in mRNA regulation.

    To analyze mRNA regulation by piRNAs in stem cell biology

    We are using Drosophila germline stem cells (GSCs), an outstanding model to study stem cells in vivo. We have demonstrated a role of Aub in GSC self-renewal and this Aub function depends on the regulation of the proto-oncogene Cbl (Rojas-Rios et al. EMBO J. 2017). We are further investigating the role of Aub and piRNAs in mRNA regulation for stem cell self-renewal and differentiation.


    Fig2 site webFigure : Scheme of mRNA regulation by Aubergine and piRNAs in Drosophila germline stem cells.


    To explore the molecular mechanisms of oculopharyngeal muscular dystrophy (OPMD) using the Drosophila model

    We are addressing the role of small RNAs and ribosomal RNAs in OPMD, as well as the role of cellular stresses. We are also using our Drosophila OPMD model to identify molecules that might have a strong potential for future treatments.

    Fig3Figure : Role of polyadenylation and deadenylation in OPMD (Chartier et al. PLOS Genetics 2015).