RNA splicing regulation by RNA modifications

How do RNA modifications regulate gene expression in the germ cells? Our RNA (epi)genetics laboratory addresses this broad question using the nematode Caenorhabditis elegans as an animal model.

Germline stem cells are essential for the survival of organisms by giving rise to offspring. Gene expression changes within the germ cells can affect embryonic development, and in some organisms, such changes are transgenerationally inherited. RNA is at the centre of many gene regulatory processes. There are currently more than 150 diverse chemical modifications found on RNA, and a greater number of proteins are required for their synthesis and recognition. Recent discoveries have shown that RNA modifications can be dynamically regulated and they have been implicated in embryonic development, longevity, neurological diseases and cancers in humans and in animal models.

The PhD project will focus on how snRNA modifications regulate isoform-specific gene expression. Our lab has shown that snRNA methylations can affect splice site choice during pre-mRNA splicing. The project will use molecular biology, genetics and RNA sequencing technologies to study how gene-specific splice site choice affects transcript isoform expression during C. elegans development.

We offer a multidisciplinary and supportive research environment. The student will have a wide range of support to learn different techniques and will interact with national and international laboratories working on RNA modifications. The student will attend conferences, seminars and multiple cross-laboratory events. The student will be given internal and external mentorship and career development support. Our RNA (epi)genetics laboratory is funded by a prestigious UKRI Future Leaders Fellowship and provides generous resources and instruments. This project is particularly suitable for students interested in RNA biology, biochemistry and Oxford Nanopore sequencing.

References

Shen, A., Hencel, K., Parker, M. T., Scott, R., Skukan, R., Adesina, A. S., Metheringham, C. L., Miska, E. A., Nam, Y., Haerty, W., Simpson, G. G. & Akay, A. U6 snRNA m6A modification is required for accurate and efficient splicing of C. elegans and human pre-mRNAs. Nucleic Acids Research gkae447 (2024). doi:10.1093/nar/gkae447

Cao, X., Zhang, Y., Ding, Y. & Wan, Y. Identification of RNA structures and their roles in RNA functions. Nat Rev Mol Cell Biol 1–18 (2024). doi:10.1038/s41580-024-00748-6

Navarro, I. C., Tuorto, F., Jordan, D., Legrand, C., Price, J., Braukmann, F., Hendrick, A. G., Akay, A., Kotter, A., Helm, M., Lyko, F. & Miska, E. A. Translational adaptation to heat stress is mediated by RNA 5-methylcytosine in Caenorhabditis elegans. EMBO J. 40, e105496 (2021).

van Delft, P., Akay, A., Huber, S. M., Bueschl, C., Rudolph, K. L. M., Di Domenico, T., Schuhmacher, R., Miska, E. A. & Balasubramanian, S. The Profile and Dynamics of RNA Modifications in Animals. Chembiochem 18, 979–984 (2017).

Wilkinson, M. E., Charenton, C. & Nagai, K. RNA Splicing by the Spliceosome. Annu. Rev. Biochem. 89, 359–388 (2020).