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GW4 BioMed MRC DTP PhD studentship: KAP1-long non-coding RNA chromatin regulatory complexes control neurogenesis


Department of Biology & Biochemistry

About the Project

This project is one of a number that are in competition for funding from the ‘GW4 BioMed MRC Doctoral Training Partnership’ which is offering up to 17 studentships for entry in October 2021.

The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities. More information may be found here: https://www.gw4biomed.ac.uk/.

SUPERVISORY TEAM:

Dr Keith Vance (lead), University of Bath, Department of Biology & Biochemistry https://researchportal.bath.ac.uk/en/persons/keith-vance
Dr Karim Malik, University of Bristol, School of Cellular and Molecular Medicine
Prof Caleb Webber, Cardiff University, School of Medicine, UK Dementia Research Institute

THE PROJECT:

Adult neural stem cells (NSCs), located in the brain ventricular zone-subventricular zone (VZ-SVZ), produce neurons throughout life. VZ-SVZ NSCs can be stimulated by brain injury and neurodegeneration to replace damaged neurons and limit harm; but can also generate brain cancers. VZ-SVZ NSCs have great potential in regenerative medicine to reduce neuronal damage and functional loss. The prevalence of age-related neurodegeneration is predicted to rise dramatically over the next few decades with an increase in population age. A greater molecular understanding of the mechanisms controlling adult neurogenesis is urgently required so that new treatment strategies can be developed for brain diseases.

We recently showed that Kap1 (Trim28) and the VZ-SVZ expressed long non-coding RNA (lncRNA) Paupar are critical regulators of adult neurogenesis in mouse. KAP1 is an essential chromatin regulatory protein that is required for embryonic brain development and adult brain function, whilst lncRNAs are a new class of gene expression regulators with important functions in adult stem cells and cancer. Our work showed that Paupar binds and modulates KAP1 chromatin regulatory function to control the expression of shared genes important for NSC proliferation and differentiation, and predicted that distinct lncRNA-KAP1 chromatin complexes act genome-wide to regulate adult neurogenesis (1, 2).

The proposed project will build on these findings to investigate the wider role of KAP1-lncRNA interaction networks in the control of NSC self-renewal and neuronal differentiation. We will identify and classify the genome-wide set of lncRNAs that associate with KAP1 in the neuronal lineage and prioritise a subset of conserved lncRNAs for functional analysis. CRISPR interference and anti-sense oligonucleotides will be used to deplete the expression of a subset of orthologous lncRNAs and phenotypic assays performed to define their function in mouse Neuro-2A and human SHSY5Y neuroblastoma cells, an aggressive childhood tumour caused by impaired NSC differentiation. In addition, the mechanisms of KAP1-lncRNA mediated transcription and chromatin regulation important for neurogenesis will also be investigated.

This project will discover new neuro-developmental regulatory mechanisms and identify novel KAP1-associated lncRNA regulators of neurogenesis with potential to be targeted for the development of new therapies to treat neurodegeneration, brain injury and neuroblastoma.

APPLICATIONS:

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 area appropriate to the skills requirements of the project.

IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form: https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-doctoral-training-partnership-student-appl-2

You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding form the DTP will be required to submit an application to study at Bath.

More information on the application process may be found here:
https://www.gw4biomed.ac.uk/doctoral-students/

APPLICATIONS CLOSE AT 17:00 ON 23 NOVEMBER 2020.

Funding Notes

UK students will be considered for a full 3.5-year studentship consisting of UK tuition fees, a Research and Training Support Grant of £2000-£5000 per annum and a stipend (£15,285 per annum for 2020/21, updated each year).

International applicants (including EU applicants) are also eligible to apply but will be required to pay the difference between the Home UKRI tuition fee View Website and the applicable University of Bath Overseas tuition fee rate View Website. Confirmation of ability to fund the tuition fee difference will be required.

References

[1] Pavlaki, I., Alammari, F., Sun, B., Clark, N., Sirey, T., Lee, S., Woodcock, D.J., Ponting, C.P., Szele, F.G. and Vance, K.W. (2018) The long non-coding RNA Paupar promotes KAP1-dependent chromatin changes and regulates olfactory bulb neurogenesis. EMBO J, doi: 10.15252/embj.201798219.

[2] Vance, K.W., Sansom, S.N., Lee, S., Chalei, V., Kong, L., Cooper, S.E., Oliver, P.L. and Ponting, C.P. (2014) The long non-coding RNA Paupar regulates the expression of both local and distal genes. EMBO J, 33, 296-311.


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