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*EASTBIO* How does a mammalian cell physically organise the complex processes of gene expression and regulation?

  • Full or part time
    Dr J Sleeman
  • Application Deadline
    Sunday, January 05, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

BBSRC Thematic Group: Frontier Bioscience
Accurate gene expression and regulation in mammalian cells is a hugely complex process, essential for cellular and organismal homeostasis. The physical organisation of gene expression within the cell, in turn, requires precise and complex compartmentalization within the nucleus and cytoplasm of the cell. This compartmentalization occurs using a number of sub-cellular structures that are not formed using membranes, but by processes of phase separation driven by the interactions between RNA and protein molecules.

In a number of progressive human diseases associated with ageing, faulty messenger RNA molecules containing expanded repeat sequences (for example >100 copies of the triplet CUG in Myotonic Dystrophy Type 1 and expansion within the C9orf72 locus associated with Amyotrophic Lateral Sclerosis) form foci in the nucleus of the cell. These foci interfere with gene expression and regulation, although the details of how this happens are not understood. Pre-mRNA splicing is widely reported to be affected, but other essential processes such as polyadenylation; 5’ capping; intra-cellular transport and mRNA degradation have not been widely studied in this context. We have recently discovered that the presence of these expanded RNA foci also alters the physical structure, dynamics and molecular composition of a number of phase separated cellular structures required for correct gene regulation. We have generated novel cell lines in which we can induce these foci to use as a model to investigate cellular structures and molecular pathways required for accurate gene expression and regulation.

This project will use these novel cell lines, and generate related cell lines, to address a number of linked questions.

1) What is the biophysical nature of the disease-associated RNA foci?
2) Which aspects of gene expression and regulation are affected by the presence of the foci?
3) In what way are the morphology and dynamic behaviour of phase-separated cellular structures affected by the foci?

Taken together, the answers to these questions will provide valuable insights into the fundamental cellular organisation of gene expression and regulation.

The training provided by the project will include molecular biology; cell culture; quantitative proteomics; microscopy including 3 dimensional time-lapse, superresolution (Airyscan and SIM) and photokinetic analyses; data analysis and electron microscopy.

Informal enquiries are strongly encouraged and should be made by email to Dr Judith Sleeman.

Funding Notes

This project is eligible for the EASTBIO Doctoral Training Partnership: View Website

This opportunity is only open to UK nationals (or EU students who have been resident in the UK for 3+ years immediately prior to the programme start date) due to restrictions imposed by the funding body.

Apply by 5.00 pm on 5 January 2020 following the instructions on how to apply at: View Website

Please also upload the EASTBO Application Form as an additional document to the University of St Andrews online Application.

Informal inquiries to the primary supervisor are very strongly encouraged.

References

The Cajal body and the nucleolus: "In a relationship" or "It's complicated"?
Trinkle-Mulcahy L, Sleeman JE.
RNA Biol. 2017 Jun 3;14(6):739-751. doi: 10.1080/15476286.2016.1236169.

Liquid phase condensation in cell physiology and disease.
Shin Y, Brangwynne CP.
Science. 2017 Sep 22;357(6357). pii: eaaf4382. doi: 10.1126/science.aaf4382

How good is research at University of St Andrews in Biological Sciences?

FTE Category A staff submitted: 50.45

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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