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Going across temporal scales: how are oscillatory dynamics of protein expression decoded in the expression of downstream genes in neurogenesis?


   Faculty of Biology, Medicine and Health

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  Prof N Papalopulu, Prof Hilary Ashe  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

In recent years, our understanding of gene expression dynamics has been transformed by single-cell, molecular and imaging technologies. It was thought that genes are simply “on” or “off”, but we now appreciate that the dynamics are more complex. For example, it is known that when a gene is “on|”, transcription of DNA into mRNA is not a smooth process but occurs in stochastic “bursts” of activity followed by silent periods. In addition, it has been discovered that protein dynamics, are also not smooth and may show periodic fluctuations with short periodicity of a few hours, which are called ultradian oscillations. Oscillations are thought to be a very versatile way for the cell to receive molecular information, because in addition to the mean level of expression, other characteristics of the protein dynamics, such as the amplitude, the frequency and the phase with other oscillators can be interpreted by downstream genes. Oscillations are thought to keep the cell in a flexible, primed, state but other functions have also been proposed.

However, how does the transcriptional machinery respond to oscillatory transcription factor dynamics is completely unknown. How do the oscillatory protein dynamics interface with the evidence of bursty stochastic mRNA expression? To gain insight into these questions, we propose to simultaneously monitor with live imaging the oscillatory dynamics of a transcription factor, neurogenin, at the protein level and the transcriptional response of a downstream target, neuroD. Both will be assayed by live imaging, in real time. We already have a neurogenin reporter that can be used for live imaging of the protein dynamics and during this project we will make an endogenous reporter of the neuroD transcription using the MS2 system. We will also develop tools (optogenetics and/or chemical tools) to manipulate the dynamics at will in order to assess their functional importance.

Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with previous laboratory experience, particularly in cell culture and molecular biology, are particularly encouraged to apply.

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 Genetics

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.

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/”

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 www.internationalphd.manchester.ac.uk


Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/

References

Biga, V., Hawley, J., Soto, X., Johns, E., Han, D., Bennett, H., Adamson A.D., Kursawe, J., Glendining, P., Manning C.S., Papalopulu, N. (2021) A dynamic, spatially periodic, micro-pattern of HES5 underlies neurogenesis in the mouse spinal cord. Mol Syst Biol 17:e9902.
Soto, X., Biga, V., Kursawe, J., Lea, R., Doostdar, P., Thomas, R., Papalopulu, N. (2020) Dynamic properties of noise and Her6 levels are optimized by miR-9, allowing the decoding of the Her6 oscillator. EMBO J. 39:e103558.
Manning, C.S., Biga, V., Boyd, J., Kursawe, J., Ymisson B., Spiller, D.G., Sanderson, C.M., Galla T., Rattray, M., Papalopulu N. (2019) Quantitative single-cell live imaging links HES5 dynamics with cell-state and fate in murine neurogenesis. Nat Comm 10:2835.
Vinter DJ, Hoppe C, Minchington TG, Sutcliffe C, Ashe HL. (2021) Dynamics of hunchback translataion in real-time and at single-mRNA resolution in the Drosophila embryo Development. 2021 Sep 15;148(18):dev196121.
Hoppe C, Bowles JR, Minchington TG, Sutcliffe C, Upadhyai P, Rattray M, Ashe HL.(2020) Modulation of the promoter activatior rate dictates the transcriptional response to graded BMP Signalling levels in the Drosophila Embryo
Dev Cell. 2020 Sep 28;54(6):727-741.e7.
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