A novel role in mitochondrial homeostasis for the anti-ageing factor RBBP5

About the Project

The mitochondrion has evolved from the endosymbiotic interaction between an alpha-proteobacterium and an archaeon. One major event during this evolution was the transferring of genes from the symbiont to the host. The mitochondrial genome has retained about a dozen of protein coding genes, but about 1000 different proteins form the mitochondrial proteome. An unbalanced mitochondrial proteome can be catastrophic if not repaired by the mitochondrial stress response. The mitochondrial stress response increases expression of genes that restores and protects the mitochondria. Left uncorrected, the unbalance proteome will cause premature ageing and death. Therefore, the mitochondrial stress response is critical to maintain mitochondrial homeostasis and prevent premature ageing.My lab identified RBBP5 as an anti-ageing factor crucial to maintain mitochondrial function. It is also required to induce a specific mitochondrial stress response called the mitochondrial Unfolded Protein Response (mitoUPR). The mitoUPR in C. elegans protects the mitochondria and extend lifespan. RBBP5 is essential to methylation at histone 3 lysine 4 (H3K4). H3K4 methylation is associated with transcriptionally active genes and is an evolutionary conserved epigenetic modification. Your project will investigate the mechanism by which RBBP5 prevents ageing. Your experiments will focus on mitochondrial homeostasis and the associated mitoUPR. You will use both C. elegans to define the set of genes regulated by RBBP5 at both transcriptional and translational levels. A subset of these will be tested in tissue culture systems. You will use auxin-inducible degron versions of rbbp-5 and set-16, important components of the H3K4 methylation complex, to investigate the role of H3K4 methylation in specific tissues at specific time. You will then couple these findings with deep sequencing such as ATAC-seq and RNA-seq as well as proteomic technologies to unravel the molecular mechanism implicated. Our preliminary data indicate that neurons are the main tissue where H3K4 methylation regulate mitochondrial stress. This project could impact on our fundamental understanding of neuronal degenerations linked to ageing. In summary, the selected student will be trained in a range of molecular biology, genomic and proteomic approaches to unravel fundamental biological principles central to mitochondrial function and ageing.

Entry requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related subject area. Master degree or lab experience is preferable, but not necessary.

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How 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 https://www.bmh.manchester.ac.uk/study/research/programmes/integrated-teaching/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered.

If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk.

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

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

References

Cryptic genetic variation of expression quantitative trait locus architecture revealed by genetic perturbation in Caenorhabditis elegans. Van Wijk, MH, Riksen JAG, Elvin M, Poulin GB, Maulana MI, Kammenga JE, Snoek BL, Sterken MG. G3(Bethesda) 2023 May 2 2;13(5)

The mTOR-S6 kinase pathway promotes stress granule assembly. Sfakianos AP, Mellor LE, Pang YF, Krtisiligkou P, Needs H, Abou-Hamdan H, Désaubry L, Poulin GB, Ashe MP, Whitmarsh AJ. Cell Death Differ 2018 Nov; 25 (10)

Natural Genetic Variation Influences Protein Abundances in C. elegans Developmental Signalling Pathways. Singh KD, Roschitzki B, Snoek LB, Grossmann J, Zheng X, Elvin M, Kamkina P, Schrimpf SP, Poulin GB, Kammenga JE, Hengartner MO. PLoS One. 2016 Mar 17;11(3)

A nuclear sensor of mitochondrial function. Monaghan RM, Poulin GB, Whitmarsh AJ. Oncotarget. 2015 Jun 30;6(18)

Monaghan RM, Barnes RG, Fisher K, Andreou T, Rooney N, Poulin GB, Whitmarsh AJ. A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity. Nat Cell Biol, 2015. Jun;17(6)