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Defining the physiological role and regulation of biological methylations


Faculty of Biology, Medicine and Health

About the Project

The regulation of gene expression and function operates at multiple levels. Metabolic pathways in the cell generate metabolites that directly affect DNA, RNA and proteins, regulating the expression and function of many genes, often feeding back on the very enzymes that catalysed their synthesis. The precursors of these key regulatory metabolites, or the key metabolites themselves, are usually obtained from the diet. Thus, in our body there is an intimate integration between our diet, our physiology and behaviour, and yet, how this integration operates remains obscure in many ways. What is clear is that, when the link between essential nutrients and gene expression is disrupted, pathologies including cardiovascular diseases, diabetes, cancer and neurological problems arise.

This project is seeking to define how the essential amino acid methionine and vitamin B9 regulate our physiology and behaviour. These two nutrients can regulate gene expression and function by acting on DNA and proteins by a mechanism known as methylation, i.e. the addition of a methyl group to specific nucleotides or amino acids. Methylated nucleotides can also be found on RNAs, but whether and how this methylation can be regulated, and whether it is affected by our diet is unknown. Our previous investigations have revealed that methyl metabolism, and especially mRNA methylation, is critical for biological rhythms in organisms throughout evolution, from bacteria to humans. The project will use these discoveries as a starting point to investigate the physiological function of RNA methylation, how it is regulated by our diet, and what pathologies arise when it is disrupted.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in biology, life sciences, pharmacology or related subjects. Candidates who already have experience in experimental biology are encouraged to apply.

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Molecular Biology


For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk




Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Fustin JM, Doi M, Yamaguchi Y, Hida H, Nishimura S, Yoshida M, Isagawa T, Morioka MS, Kakeya H, Manabe I, Okamura H. RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell. 2013 Nov 7;155(4):793-806. doi: 10.1016/j.cell.2013.10.026.

2. Fustin, J-M, Kojima, R, Itoh, K, Chang, H-Y, Ye, S, Zhuang, B, Oji, A, Gibo, S, Narasimamurthy, R, Virshup, D, Kurosawa, G, Doi, M, Manabe, I, Ishihama, Y, Ikawa, M & Okamura, H. Two Ck1δ transcripts regulated by m6A meth-ylation code for two antagonistic kinases in the control of the circadian clock. Proc Natl Acad Sci U S A. 2018 Jun 5;115(23):5980-5985. doi: 10.1073/pnas.1809838115

3. Fustin JM, Ye S, Rakers C, Kaneko K, Fukumoto K, Yamano M, Versteven M, Grünewald E, Cargill SJ, Tamai TK, Xu Y, Jabbur ML, Kojima R, Lamberti ML, Yoshioka-Kobayashi K, Whitmore D, Tammam S, Howell PL, Kageyama R, Matsuo T, Stanewsky R, Golombek DA, Johnson CH, Kakeya H, van Ooijen G, Okamura H. Methylation deficiency disrupts biological rhythms from bacteria to humans. Commun Biol. 2020 May 6;3(1):211. doi: 10.1038/s42003-020-0942-0.

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