(BBSRC DTP) Defining the roles of mRNA methylation in circadian physiology and inflammation at The University of Manchester on FindAPhD.com

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Dr Jean-Michel Fustin, Prof David Bechtold, Dr J Gibbs, Dr K Piper Hanley No more applications being accepted Competition Funded PhD Project (Students Worldwide)

Manchester United Kingdom Cell Biology Genetics Immunology Molecular Biology Neuroscience

About the Project

Methylation is a pervasive biochemical modification targeting virtually all types of molecules in our cells. A key metabolic pathway called the “methyl cycle” synthesises S-adenosylmethionine (SAM), the methyl donor co-substrate used by over 200 substrate-specific methyltransferases described so far in humans.

While the role and regulation of histone and DNA methylation in the epigenetic control of gene expression are relatively well understood, the methylation of messenger RNA (mRNA) remain an obscure event in biology’s central dogma. It is known that a handful of nucleotides at key loci in mRNA are methylated, each by a specific methyltransferase, but what the physiological functions of these methylated nucleotides are, and how they are regulated, is unknown. What is clear however, is that these methylated nucleotides in mRNA are essential for development and survival in many species.

Our previous investigations have revealed that biological rhythms in many organisms from bacteria to humans are intimately linked to methyl metabolism: pharmacological disruption of methyl metabolism causes our biological rhythms to slow down dramatically, and eukaryotes down to unicellular algae are as sensitive as us¹. We have also shown that mRNA and histone methylation are important links between the methyl cycle and biological rhythms in vitro^2,3,4.

This PhD project aims to further define the physiological function of selected methylated nucleotides by studying the behaviour, physiology and pathologies of genetically altered mice in which deficiencies in these methylated nucleotides can be triggered from the adult stage, thereby circumventing developmental problems caused by a too premature deficiency. While the research will initially focus on biological rhythms, there will be opportunities to investigate other interesting inflammatory phenotypes or pathologies developed by these mice. Cell culture-based experiments will complement and often precede animal experiments to investigate molecular and cell.

https://www.research.manchester.ac.uk/portal/jean-michel.fustin.html

https://www.research.manchester.ac.uk/portal/david.bechtold.html

https://www.research.manchester.ac.uk/portal/julie.gibbs.html

https://www.research.manchester.ac.uk/portal/karen.piperhanley.html

Entry Requirements

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.

Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.

How To Apply

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

Funding Notes

Funding will cover tuition fees and stipend only. This scheme is open to both UK and international applicants. However, we are only able to offer a limited number of studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1. 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.
2. Greco CM, Cervantes M, Fustin JM, Ito K, Ceglia N, Samad M, Shi J, Koronowski KB, Forne I, Ranjit S, Gaucher J, Kinouchi K, Kojima R, Gratton E, Li W, Baldi P, Imhof A, Okamura H, Sassone-Corsi P. S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling. Sci Adv. 2020 Dec 16;6(51):eabc5629. doi: 10.1126/sciadv.abc5629.
2. Fustin JM, Kojima R, Itoh K, Chang HY, 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 methylation 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.1721371115.
3. 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.