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ControlbypiRNA - Molekulare Aspekte der mRNA-Regulation durch piRNAs und RNA-bindende Proteine in Drosophila

Fachliche Zuordnung Biochemie
Entwicklungsbiologie
Förderung Förderung von 2015 bis 2022
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 284014685
 
Erstellungsjahr 2019

Zusammenfassung der Projektergebnisse

Understanding mRNA regulation using Drosophila embryo as a model. Gene regulation at the post-transcriptional level is essential in many biological processes. One major regulatory mechanism involves cytoplasmic variations of mRNA poly(A) tail length, which affects both stability and translation. This regulation is essential for early embryogenesis, which depends on regulation of maternal mRNAs. We have used the Drosophila embryo as a model system to investigate post-transcriptional regulation. This model allows the utilization of both cutting-edge genetic techniques to address biological questions in vivo as well as biochemical approaches. The project aimed at addressing the molecular mechanisms of mRNA regulation by RNA binding proteins and small non-coding RNAs. In particluar we have previously reported that a specific class of small non-coding RNAs, the piRNAs (Piwi-interacting RNAs, 24-30nt long), are involved in the repression of maternal mRNAs in the early embryo. piRNAs have been found in germ cells of many species and a large proportion of them are produced from transposable element sequences. Their primary function is to repress transposable elements in the germline. We have uncovered an unexpected role of the piRNA pathway in gene regulation in the embryo: piRNAs produced from transposable elements target and regulate maternal mRNAs. The objective of this project was to unravel the molecular mechanisms of this regulation. Multidiciplinary approaches to decipher mRNA regulation in the Drosophila embryo. Our collaborative project aims at addressing the molecular mechanisms underlying mRNA regulation by piRNAs and RNA binding proteins. We have investigated both mRNA decay and translational repression, as well as an opposite role of the piRNA pathway in mRNA stabilization. Our project involves genetics, cell biology, imaging, molecular and biochemical approaches, as well as mass spectrometry for the analysis of protein complexes. This wide range of approaches allows to establish a link between specific mechanisms of mRNA regulation and their function in developmental processes. This project brought key information for our understanding of both gene regulation at the post-transcriptional level and the function of small non-coding RNAs. Key results from this project are as follows. We have identified the complex involved in the translational repression of nanos maternal mRNA in the embryo. Importantly we show that translational repression involves coating of the mRNA by the RNA helicase Me31B and its cofactor Trailer hitch (Tral). - We have identified another developmental process where piRNAs and PIWI proteins are required for cellular mRNA regulation. We show that the piRNA pathway is required for germline stem cell self-renewal through translational repression of a proto-oncogene. - We have identified a role of piRNAs in mRNA stabilization, while small non-coding RNAs and piRNAs were known for their role in mRNA silencing (mRNA decay and translational repression). This new function of piRNAs is required for germ cell development in the Drosophila embryo. - In addition, we identified a new function of PIWI proteins in translational activation. These results were unexpected since piRNAs were know to regulate mRNAs through their stability. Therefore, these data identify a new mechanism of action of piRNAs for mRNA regulation. This project allowed us to get a new ANR PRCI grant in 2019 with Germany. It also contributed to three successful EMBO Workshop applications to organize the EMBO piRNA Workshop in 2016, 2018 and 2020. This project allowed to produce three publications published in RNA, EMBO J. and Nature Communications. In addition, four invited reviews or book chapters were written and published in the frame of this project, among which a comprehensive review on the role of piRNAs in mRNA regulation published in Development. Finally, two preprints have been deposited this week on bioRxiv and should be published in the near future.

Projektbezogene Publikationen (Auswahl)

 
 

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