piRNAs are regulators of metabolic reprogramming in stem cells
Rojas-Ríos P, Chartier A, Enjolras C, Cremaschi J, Garret C, Boughlita A, Ramat A, Simonelig M
Régulation des ARNm et Développement
Génétique, biologie cellulaire 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.
Figure : 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.
Vidéos
Publications de l'équipe
Spatial organization of translation and translational repression in two phases of germ granules
Anne Ramat, Ali Haidar, Céline Garret, Martine Simonelig
The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response.
Naït-Saïdi R, Chartier A, Abgueguen E, Guédat P, Simonelig M
Emerging roles and functional mechanisms of PIWI-interacting RNAs.
Wang X, Ramat A, Simonelig M, Liu MF
Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy.
Ribot C, Soler C, Chartier A, Al Hayek S, Naït-Saîdi R, Barbezier N, Coux O, Simonelig M
Functions of PIWI Proteins in Gene Regulation: New Arrows Added to the piRNA Quiver
Anne Ramat, Martine Simonelig
The PIWI protein Aubergine recruits eIF3 to activate translation in the germ plasm
Anne Ramat, Maria-Rosa Garcia-Silva, Camille Jahan, Rima Naït-Saïdi, Jérémy Dufourt, Céline Garret, Aymeric Chartier, Julie Cremaschi, Vipul Patel, Mathilde Decourcelle, Amandine Bastide, François Juge & Martine Simonelig
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
piRNAs and PIWI proteins: regulators of gene expression in development and stem cells.
Rojas-Ríos P, Simonelig M
Dicer-2 promotes mRNA activation through cytoplasmic polyadenylation.
Coll O, Guitart T, Villalba A, Papin C, Simonelig M, Gebauer F
iCLIP of the PIWI Protein Aubergine in Drosophila Embryos.
Barckmann B, Dufourt J, Simonelig M
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
Aubergine and piRNAs promote germline stem cell self-renewal by repressing the proto-oncogene Cbl.
Rojas-Ríos P, Chartier A, Pierson S, Simonelig M
Translational repression of the Drosophila nanos mRNA involves the RNA helicase Belle and RNA coating by Me31B and Trailer hitch
Götze M, Dufourt J, Ihling C, Rammelt C, Pierson S, Sambrani N, Temme C, Sinz A, Simonelig M, Wahle E.
Measurement of mRNA Poly(A) Tail Lengths in Drosophila Female Germ Cells and Germ-Line Stem Cells
Chartier A, Joly W, Simonelig M.
Translational Control of Autophagy by Orb in the Drosophila Germline
Rojas-Rios, P., Chartier, A., Pierson, S., Severac, D., Dantec, C., Busseau, I., Simonelig, M.
Aubergine iCLIP Reveals piRNA-Dependent Decay of mRNAs Involved in Germ Cell Development in the Early Embryo
Barckmann,B., Pierson,S., Dufourt, J., Papin, C., Armenise, C., Port, F., Grentzinger, T., Chambeyron, S., Baronian, G., Desvignes, JP., Curk, T., Simonelig, M.
Mitochondrial dysfunction reveals the role of mRNA poly(a) tail regulation in oculopharyngeal muscular dystrophy pathogenesis
Chartier A, Klein P, Pierson S, Barbezier N, Gidaro T, Casas F, Carberry S, Dowling P, Maynadier L, Bellec M, Oloko M, Jardel C, Moritz B, Dickson G, Mouly V, Ohlendieck K, Butler-Browne G, Trollet C, Simonelig M.
piRNAs, master regulators of gene expression
Simonelig M
Deadenylation of mRNA by the CCR4-NOT complex in Drosophila: molecular and developmental aspects
Temme, C., Simonelig, M., Wahle E.
The CCR4 Deadenylase Acts with Nanos and Pumilio in the Fine-Tuning of Mei-P26 Expression to Promote Germline Stem Cell Self-Renewal
Joly, W,, Chartier,A., Rojas-Rios, P., Busseau,I., Simonelig, M.
Control of maternal mRNA stability in germ cells and early embryos
Barckmann B, Simonelig M.
Animal models in therapeutic drug discovery for oculopharyngeal muscular dystrophy
Chartier A, Simonelig M.
PABPN1 shuts down alternative poly(A) sites
Simonelig, M
Maternal-to-zygotic transition: soma versus germline.
Simonelig, M.
Embryonic development is controlled by small non-coding RNAs derived from transposable elements
Papin C, Simonelig M.
Developmental functions of piRNAs and transposable elements: A Drosophila point-of-view.
Simonelig, M
Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients.
Anvar SY, 't Hoen PA, Venema A, van der Sluijs B, van Engelen B, Snoeck M, Vissing J, Trollet C, Dickson G, Chartier A, Simonelig M, van Ommen GJ, van der Maarel SM, Raz V.
Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy.
Barbezier N, Chartier A, Bidet Y, Buttstedt A, Voisset C, Galons H, Blondel M, Schwarz E, Simonelig M.
Maternal mRNA deadenylation and decay by the piRNA pathway in the early Drosophila embryo
Rouget, C., Papin, C., Boureux, A., Meunier, A.C., Franco, B., Robine, N., Lai, E.C., Pelisson, A. & Simonelig, M.
Subunits of the Drosophila CCR4-NOT complex and their roles in mRNA deadenylation
Temme, C., Zhang, L., Kremmer, E., Ihling, C., Chartier, A., Sinz, A., Simonelig, M., Wahle, E.
Prevention of oculopharyngeal muscular dystrophy by muscular expression of Llama single-chain intrabodies in vivo.
Chartier, A., Raz, V., Sterrenburg, E., Verrips, CT., van der Maarel, SM., Simonelig, M
PAP- and GLD-2-type poly(A) polymerases are required sequentially in cytoplasmic polyadenylation and oogenesis in Drosophila
Benoit, P., Papin, C., Kwak, JE., Wickens, M., Simonelig, M.
Bicaudal-C recruits CCR4-NOT deadenylase to target mRNAs and regulates oogenesis, cytoskeletal organization, and its own expression
Chicoine, J., Benoit, P., Paliouras, M., Gamberi, C., Simonelig, M. and Lasko, P.
Oskar allows nanos mRNA translation in Drosophila embryos by preventing its deadenylation by Smaug/CCR4.
Zaessinger S, Busseau I, Simonelig M.
A Drosophila model of oculopharyngeal muscular dystrophy reveals intrinsic toxicity of PABPN1.
Chartier A, Benoit B, Simonelig M.
An essential cytoplasmic function for the nuclear poly(A) binding protein, PABP2, in poly(A) tail length control and early development in Drosophila
Benoit, B., Mitou, G., Chartier, A., Temme, C., Zaessinger, S., Wahle, E., Busseau I., Simonelig, M.
A complex containing the CCR4 and CAF1 proteins is involved in mRNA deadenylation in Drosophila
Temme, C., Zaessinger, S., Meyer, S., Simonelig, M., Wahle, E.
Control of poly(A) polymerase level is essential to cytoplasmic polyadenylation and early development in Drosophila
Juge, F., Zaessinger, S., Temme, C., Wahle, E. and Simonelig, M.
Chimeric human CstF-77/Drosophila Suppressor of forked proteins rescue suppressor of forked mutant lethality and mRNA 3' end processing in Drosophila
Benoit, B., Juge, F., Iral, F., Audibert, A. and Simonelig, M.
Tissue-specific autoregulation of Drosophila suppressor of forked by alternative poly(A) site utilization leads to accumulation of the Suppressor of forked protein in mitotically active cells
Juge, F., Audibert, A., Benoit, B. and Simonelig, M.
The Drosophila poly(A)-binding protein II is ubiquitous throughout Drosophila development and has the same function in mRNA polyadenylation as its bovine homolog in vitro.
Benoit, B., Nemeth, A., Aulner, N., Kuhn, U., Simonelig, M., Wahle, E. and Bourbon, H.M.
The suppressor of forked gene of Drosophila, which encodes a homologue of human CstF-77K involved in mRNA 3'-end processing is required for progression through mitosis.
Audibert, A. and Simonelig, M.
Autoregulation at the level of mRNA3'-end formation of the suppressor of forked gene of Drosophila melanogaster is conserved in Drosophila virilis.
Audibert, A. and Simonelig, M.
The suppressor of forked protein of Drosophila, a homologue of the human 77K protein required for mRNA 3'-end formation, accumulates in mitotically-active cells.
Audibert, A., Juge, F. and Simonelig, M.
Thèses et hdr
Le rôle du stress oxidatif et du réticulum endoplasmique dans la DMOP : mécanismes moléculaires et traitements pharmacologiques. 23/11/2022
Soutenue par Rima Nait-Saidi le 23-11-2022
Mécanismes de la régulation traductionnelle médiée par la voie piARN dans le contrôle de la mise en place de l'axe antéro-postérieur chez Drosophila melanogaster 29/03/2019
Soutenue par Camille Jahan le 29-03-2019
