Bioinformatic analysis of the function of mRNA poly(A) tails

About the Project

Every molecular biology textbook will tell you that messenger RNAs are appended by a 200-250 nucleotide poly(A) tail in the nucleus and exported to the cytoplasm, where the poly(A) tail promotes translation of the mRNA and is gradually removed. Once the poly(A) tail falls below 20-25 nt, mRNA degradation is triggered. In recent years, the advent of whole transcriptome poly(A) tail measurements has somewhat dented this traditional view, as we and others found that not all mRNAs leave the nucleus with 200A tails and that the correlation between translational efficiency and poly(A) tail size is weak in most cell types. Nevertheless, therapeutic mRNAs, such as the Covid vaccines, benefit greatly from having a poly(A) tail and the polyadenylation inhibitor cordycepin has profound effects on cell growth and immune responses.

To investigate these discrepancies, we conducted Nanopore sequencing on cytoplasmic and chromatin bound RNA in a BBSRC funded project to investigate the role of the poly(A) tail in mRNA stability and translation. Preliminary analysis of these data in conjunction with Ribo-Seq and mRNA stability data indicates that instead of the size, the changes in size of the poly(A) tail are important for its effect on mRNA fate. Moreover, analysis of cordycepin treated cells suggests that polyadenylation affects specific subsets of mRNAs. In this project, you will do a deeper analysis of these data to tease out regulatory mechanisms by refining the bioinformatic analysis and do new analyses, for example determining whether particular RNA binding proteins are likely to be involved in mRNA specific regulation. This project will be predominantly be bioinformatic analysis and give you desirable skills in large data manipulatio. In addition, you can also do some lab work to obtain a large datasets of your own, for instance to investigate the role of protein synthesis in poly(A) tail regulation by treating cells with a protein synthesis inhibitor. You can potentially finish your PhD by validating a hypothesis that you have generated using bioinformatics in the laboratory. This project is likely to change our understanding of the relationship between mRNA polyadenylation, deadenylation and gene expression.

Funding Notes

We will offer help with scholarship applications to successful applicants, if required.

References

Singhania, R., Thorn, G.J., Williams, K., Gandhi, R.D., Daher, C., Barthet-Barateig, A., Parker, H.N., Utami, W., Al-Siraj, M., Barrett, D.A., Wattis, J.A.D. and De Moor, C.H. (2019). Nuclear poly(A) tail size is regulated by Cnot1 during the serum response. BioRxiv.

Lawrence, S., Lin, J., Khurshid, A., Utami, W., Singhania, R., Ashraf, S., Thorn, G.J., Mangangcha, I.R., Spriggs, K., Kim, D.-H., Barrett,D. and De Moor, C.H. (2025) Cordycepin generally inhibits growth factor signal transduction in a systems pharmacology study. FEBS Letters, 599, 415–435.

Radhi, M., Ashraf, S., Lawrence, S., Arendt-Tranholm, A., Wellham, P.A.D., Hafeez, A., Khamis A.S., Thomas, R., McWilliams, D. and De Moor, C.H. (2021) A systematic review of the biological effects of cordycepin. Molecules, 26, 5886.

Charlesworth, A., Meijer, H.A. and De Moor, C.H. (2013). Specificity factors for cytoplasmic polyadenylation. Wiley Interdisciplinary Reviews RNA 4, 437-461.