mRNA Regulation and Development

Genetics, cell biology and development

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.

PUBLICATIONS OF THE TEAM

Anti-prion Drugs Targeting the Protein Folding Activity of the Ribosome Reduce PABPN1 Aggregation.

Bamia A, Sinane M, Naït-Saïdi R, Dhiab J, Keruzoré M, Nguyen PH, Bertho A, Soubigou F, Halliez S, Blondel M, Trollet C, Simonelig M, Friocourt G, Béringue V, Bihel F, Voisset C

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Functions of PIWI Proteins in Gene Regulation: New Arrows Added to the piRNA Quiver

Anne Ramat, Martine Simonelig

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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

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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.

BELLEC Maëlle
BELLEC Maëlle
université montpellier 2

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BONTONOU Gwenaelle
BONTONOU Gwenaelle
Unil

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JAHAN Camille
JAHAN Camille

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SALEMBIER Camille
SALEMBIER Camille

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GARCIA SILVA Maria-Rosa
GARCIA SILVA Maria-Rosa
Institut Pasteur de Montevideo

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ROUGIER Marianne
ROUGIER Marianne

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BENDRIS Nawal
BENDRIS Nawal

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ROUGET Christel
ROUGET Christel

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JOLY Willy
JOLY Willy

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MITOU Geraldine
MITOU Geraldine

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BARBEZIER Nicolas
BARBEZIER Nicolas

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BERNARD Ludivine
BERNARD Ludivine

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SOLER Cedric
SOLER Cedric

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KARRICH Bouchta
KARRICH Bouchta
GReD

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MAYNADIER Laurie
MAYNADIER Laurie

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RIBOT Cecile
RIBOT Cecile

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FINOUX Anne-laure
FINOUX Anne-laure

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VILLERONCE Olivia
VILLERONCE Olivia

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KANTAR Diala
KANTAR Diala

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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).