GW4 BioMed MRC DTP PhD studentship: KAP1-lncRNA chromatin regulatory complexes control adult neurogenesis

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 18 studentships for entry in September/October 2019.

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.

SUPERVISORY TEAM:

Lead supervisor: Dr Keith Vance, Department of Biology & Biochemistry (University of Bath)
Co-supervisor: Dr Karim Malik (University of Bristol)

THE PROJECT:

Adult neural stem cells (NSCs), located in the brain ventricular zone-subventricular zone (VZ-SVZ), produce neurons throughout life and can be stimulated by brain injury and neurodegeneration to replace damaged neurons and limit harm. VZ-SVZ NSCs therefore have great potential in regenerative medicine to reduce neuronal damage and functional loss. Yet, 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 NSCs self-renewal and neurogenesis is thus required so that new treatment strategies can be developed for brain diseases.

We recently showed that KAP1 (TRIM28) forms a chromatin regulatory complex containing the VZ-SVZ long non-coding RNA (lncRNA) Paupar and that together KAP1-Paupar function as critical regulators of adult neurogenesis in mouse. Kap1 is required for embryonic brain development and adult brain function, whilst lncRNAs have emerged as a new class of gene expression regulators with important functions in adult stem cells. The proposed project will build on these key proof-of-concept experiments to investigate the wider role of KAP1-lncRNA interaction networks in the control of adult neurogenesis. We will use the cutting edge HITS-CLIP method to comprehensively identify the set of lncRNAS that associate with endogenous KAP1 in neurosphere cultures of neural stem cells. Computational genomics will then be performed to prioritise a subset of mouse-human conserved intergenic lncRNAs for functional analysis. CRISPR interference and anti-sense oligonucleotides will be used to deplete the expression of 2-3 orthologous lncRNAs in mouse Neuro-2A and human SHSY5Y neuroblastoma cells and lncRNA loss of function phenotypes characterised. In addition, we will perform chromatin and reporter analysis to dissect conserved mechanisms of KAP1-lncRNA mediated transcription and chromatin regulation. This work will systematically identify important new KAP1-associated lncRNA regulators of neurogenesis with potential to be targeted for the future development of stem cell and neuro-regenerative therapies for the treatment of neurodegeneration and brain injury.

APPLICATIONS:

Applicants for a studentship 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-dtp-student-2019

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

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.