RNA Modifications regulate gene expression

RNA modifications - also often referred to as the epitranscriptome - is currently one of the fastest growing fields in bio-chemical research. In contrast to DNA, which is stable and stores the same genetic information in all cells of the body, RNA is dynamic, quite unstable and mediates a variety of cell type-specific functions. All four RNA bases can be subjected to chemical modifications – which is not necessarily bad – and transfer RNA (tRNA) carries the most of these modifications¹.

RNA modifications affect nearly all steps of gene expression because they occur in all types of RNAs. Because the epitranscriptome often changes in response to environmental challenges, the correct spatio-temporal deposition of RNA modifications is important for normal human development ². Aberrantly placed RNA modifications contribute to severe human diseases such as metabolic disorders, neuro-developmental deficits and cancer ^3,4.

The realizations that chemical modifications functionalize RNAs and that different RNA modifications play cell type- and context-specific roles in cancer propelled RNA modification enzymes into the focus of the pharmaceutical industry ^5,6. To exploit RNA modifications for the treatment of cancer, we must understand their exact role in promotion or inhibition of tumour development and growth as well as metastasis and drug resistance.

Our hypothesis is that RNA modification pathways play central and multifunctional roles in tumour progression, metastasis and drug resistance and that targeting them provides novel therapeutic opportunities.

To test our hypothesis, we currently have three research questions:

(1) Can we identify novel cancer-relevant RNA modifications and how they modulate gene expression programs?

(2) What is the clinical importance of RNA modification pathways in primary and secondary tumours?

(3) How do distinct RNA modifications confer a survival advantage to tumour-initiating or drug resistant tumour cell populations and can we develop specific inhibitors targeting them?

1  Suzuki, T. The expanding world of tRNA modifications and their disease relevance. Nat Rev Mol Cell Biol 22, 375-392, doi:10.1038/s41580-021-00342-0 (2021).

2  Frye, M., Harada, B.T., Behm, M. & He, C. RNA modifications modulate gene expression during development. Science 361,1346-1349, doi:10.1126/science.aau1646 (2018).

3  Barbieri, I & Kouzarides, T. Role of RNA modifications in cancer. Nature Reviews Cancer 20,303-322, doi:10.1038/s41568-020-0253-2 (2020).

4  Delaunay, S. & Frye, M. RNA modifications regulating cell fate in cancer. Nat Cell Biol 21, 552-559, doi:10.1038/s41556-019-0319-0 (2019).

5  Cross, R. Epitranscriptomics: The new RNA code and the race to drug it. Chem Eng News 97, 34-39 (2019).

6  Pardi, N., Hogan, M.J., Porter, F.W. & Weissman, D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov 17, 261-279, doi:10.1038/nrd.2017.243 (2018).