1 PhD project offered in the IPP summer call 2021
RNA viruses such as flaviviruses and coronaviruses use an RNA genome that contains numerous post-transcriptional modifications, including nucleoside modifications and particular cap structures, which are crucial to viral replication. Because they mediate function in the actual virion as well as in its successors, these modifications combine aspects of both, epitranscriptomics and epigenetics. Although it is known that viral modifications affect immune evasion, translation and replication, very few have been identified and localized, and the function of yet fewer are understood in detail. Recent technological breakthroughs have now created the unique opportunity to localize these modifications, to elucidate their functions, and to evaluate manipulations with therapeutic options.
PhD project: Epitranscriptomics of viral RNA
The project will employ the latest RNA sequencing technology from both, Illumina and Nanopore, to localize modifications in the RNA genome sequence of flavivirus (Dengue) and Coronaviruses. This is conducted in cooperation with the Ruggieri lab in Heidelberg, who have access to relevant biosafety level 3 facilities to handle native viruses. After construction a “candidate map” of RNA modifications, ko cell lines of potentially responsible RNA modification enzymes will be constructed for validation, and subsequent study of the impact of modifications on mammalian immune response and viral replication. The project is connected to several research consortia, which provide support for sequencing technology. An in-house cooperation aiming at antiviral drug discovery will provide potential antiviral compounds whose activities in inhibition of RNA modification will be tested in the frame of this project.
Publications relevant to the project
Ruggieri A, Helm M, Chatel-Chaix L (2020) An epigenetic "extreme makeover": the methylation of flaviviral RNA (and beyond). RNA Biol, Online ahead of print, PMID: 33356825
Werner S, Schmidt L, Marchand V, Kemmer T, Falschlunger C, Sednev MV, Bec G, Ennifar E, Höbartner C, Micura R, Motorin Y, Hildebrandt A, Helm M (2020)Machine Learning of reverse transcription signatures of variegated polymerases allows mapping and discrimination of methylated purines in limited transcriptomes. Nucleic Acids Res, 48(7):3734-3746
Jacob D, Thüring K, Galliot A, Marchand V, Galvanin A, Ciftci A, Scharmann K, Stock M, Roignant JY, Leidel SA, Motorin Y, Schaffrath R, Klassen R, Helm M (2019) Absolute quantification of noncoding RNA by microscale thermophoresis. Angew. Chem. Int. Ed, 10.1002/anie.201814377
Helm M, Motorin Y (2017) Detecting RNA modifications in the epitranscriptome: predict and validate. Nature Reviews Genetics,18(5):275-291
Lence T, Akhtar J, Bayer M, Schmid K, Spindler L, Ho CH, Kreim N, Andrade-Navarro MA, Poeck B, Helm M & Roignant JY (2016) m6A modulates neuronal functions and sex determination in Drosophila. Nature, 540(7632):242-24