mRNA cap methylation localisation and mechanisms in gene expression and RNA therapeutics

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Lead Supervisor: Nathan Archer

We invite applications for an exciting PhD studentship in collaboration between the University of Nottingham and AstraZeneca. This project offers a blend of cutting-edge fundamental research in the rapidly evolving field of mRNA modifications (the “epitranscriptome”) and its applications in RNA therapeutics. 

In animal cells, mRNA levels are poor predictors of protein level due to the complex regulation of gene expression that occurs following transcription. A component of this post-transcriptional gene regulation is the “epitranscriptome” - the more than 150 covalent modifications that can be added to RNA during or shortly after transcription. Like epigenetic DNA modifications, RNA modifications do not typically change the information contained, but rather change the “when and where” of gene expression. Messenger RNA (mRNA) modifications are essential for finely balancing gene expression in our cells. For this reason, they are also of central importance in mRNA therapies and vaccines.  

This project aims to understand more about the enigmatic mRNA modifications found near the 5’ Cap of messenger RNA. We and others have recently shown that these are particularly important to enable the precise timing and location of mRNA translation, alongside their established role in identifying mRNA as “self”. This project defines additional Cap-adjacent modification on an otherwise “mature” mRNA, and using our tools to assay mRNA metabolism, modifications, and cell biology you will bring new understanding of how this affects gene expression. You will uncover the processes or features which define this activity to inform the next generation of mRNA therapeutics.  

Throughout your PhD and with the support of the supervisory team, you will acquire a vast range of skills from RNA sequencing, molecular cloning, mammalian cell culture, to bioinformatics and epitranscriptomics. This extensive training will place you at the forefront of understanding RNA biology and gene expression as well as at the forefront of biotechnological and pharmaceutical advancements.   

This project aligns with ongoing work to determine how animal cells fine-tune gene expression through cap-adjacent mRNA modification, understand their roles in disease, and expand the toolkit used to build RNA therapies. 

 Further information:  

• F1000, 2019 - DOI:10.12688/f1000research.17956.1 
• Nature, 2016 – DOI:10.1038/nature20577 
• Nat.Comm, 2022 - DOI:10.1038/s41467-022-28549-5 
• Cell.Sys 2016 - DOI:10.1016/j.cels.2016.10.012 

This project is no longer open for recruitment.