Deciphering the role of 2’-O-methylated nucleosides in transposon control and neuronal function

• Applicant: Professor Dr. Jean-Yves Roignant
• Subject Area: Developmental Biology ; Biochemistry
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429770405

Almost half of the human genome is comprised of transposable elements (TE), which are repeat DNA elements that have the ability to mobilize and change locations over time. Once considered “junk” or “selfish” DNA, TE are now being appreciated for their functional roles in a variety of physiological processes, which can be beneficial to the organisms but can also become pathological upon uncontrolled mobilization. Mounting evidence is emerging between increased TE mobilization in aged brain cells and neurological disorders. Epigenetic mechanisms, such as DNA methylation, and small non-coding RNAs are known to play a crucial role to limit TE activity. Alterations of RNA modifications have also been linked to brain disorders but the underlying molecular mechanisms are currently unknown. Our preliminary data indicate that the abundant RNA modification 2’-O-methylated nucleosides (Nm) prevents TE mobilization in Drosophila melanogaster and that its alterations lead to neuronal defects, suggesting a link between RNA modifications, transposon control and brain function. The objective of this project is to investigate the mechanisms of Nm in the control of TE regulation in Drosophila. More precisely, we will study the function of Nm methyltransferases (MTs) in TE regulation. The specific work package includes: i) the use of specific genetic sensors as well as genomic approaches to analyze the population of TE and small RNAs that are affected upon depletion of these MTs; ii) the identification of direct targets by complementary high throughput approaches and iii) the molecular and biochemical characterization of the interplay of this RNA modification with small RNA pathways.The new field of RNA modifications, now termed Epitranscriptomics, has made major strides to the central stage of gene expression control in the recent years. The suggested study has the potential to illuminate a yet unexplored area of their role in protecting the genome against uncontrolled mobilization of transposons and in the etiology of brain disorders. Given that MTs are well known drug-targetable enzymes this project should also open new avenues to design potential therapeutic applications.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Professor Clément Carré, Ph.D.