About the Project
Altered gene expression patterns can drive cancer progression. While changes in transcription can turn key genes on and off, splicing – by which different exons can be included into mRNAs, can affect gene function. The RNA splicing regulator Tra2β is often up-regulated in breast cancer, correlating with decreased patient survival. This project will interrogate the function of Tra2β using a new technique that can direct rapid, targeted protein degradation in vivo within breast cancer cells. This will enable us to identify the very first changes in gene expression patterns, and answer if these occur at the level of splicing, transcription or both. We predict these pathways are important: Tra2β depletion with siRNA kills the MDA-MB-231 breast cancer cell line that models triple negative metastatic disease.
In the longer term the gene expression targets of Tra2β in breast cancer that we will identify are potentially useful drug targets.
Training: This project will deliver training in global gene expression analysis (using –omic level bioinformatics skills), cell culture and genome engineering (adding degrons onto the Tra2b gene and CRISPR knockout).
Elliott lab web page https://www.ncl.ac.uk/medical-sciences/people/profile/davidelliott.html
Elliott lab twitter account: https://twitter.com/TheElliottLab
Stuart Wilson Webpage: https://www.sheffield.ac.uk/biosciences/people/mbb-staff/academic/stuart-wilson
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
https://bit.ly/3lQXR8A
References
Co-transcriptional Loading of RNA Export Factors Shapes the Human Transcriptome. Viphakone N, Sudbery I, Griffith L, Heath CG, Sims D, Wilson SA.Viphakone N, et al. Mol Cell. 2019 Jul 25;75(2):310-323.e8.
Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer. Munkley J, Li L, Krishnan SRG, Hysenaj G, Scott E, Dalgliesh C, Oo HZ, Maia TM, Cheung K, Ehrmann I, Livermore KE, Zielinska H, Thompson O, Knight B, McCullagh P, McGrath J, Crundwell M, Harries LW, Daugaard M, Cockell S, Barbosa-Morais NL, Oltean S, Elliott DJ. Elife. 2019 Sep 3;8:e47678. doi: 10.7554/eLife.47678
Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons. Best A, James K, Dalgliesh C, Hong E, Kheirolahi-Kouhestani M, Curk T, Xu Y, Danilenko M, Hussain R, Keavney B, Wipat A, Klinck R, Cowell IG, Cheong Lee K, Austin CA, Venables JP, Chabot B, Santibanez Koref M, Tyson-Capper A, Elliott DJ. Nat Commun. 2014 Sep 11;5:4760. doi: 10.1038/ncomms5760.
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