Supervisors

Lead Supervisor: Dr Sean Flynn, University of Exeter, Department of Clinical Medicine

Co-Supervisor:

Dr Jack Hardwick, University of Bristol, Department of Chemistry

Professor Jonathan Mill, University of Exeter, Department of Medicine

The GW4 BioMed2 MRC DTP is offering up to 21 funded studentships across a range of biomedical disciplines, with a start date of October 2025.

These four-year studentships provide funding for fees and stipend at the rate set by the UK Research Councils, as well as other research training and support costs, and are available to UK and International students.

About the GW4 BioMed2 Doctoral Training Partnership

The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) 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, with opportunities to participate in interdisciplinary and 'team science'. The DTP already has over 90 studentships over 6 cohorts in its first phase, along with 58 students over 3 cohorts in its second phase.

The 120 projects available for application, are aligned to the following themes;

• Infection, Immunity, Antimicrobial Resistance and Repair

• Neuroscience and Mental Health

• Population Health Sciences

 

Applications open on 10th September 2024 and close at 5.00pm on 4th November 2024.

Studentships will be 4 years full time.  Part time study is also available.

Project Information

Research Theme: Neuroscience & Mental Health

Summary:

Rett syndrome (RTT) is a neurodevelopmental disorder that causes physical and mental disability from early childhood. It is characterised by impaired motor and cognitive function and autistic-like behaviours. We have begun to appreciate that gene regulatory elements called enhancers are perturbed in RTT, but the precise mechanisms involved remain unclear. This project will investigate how mutations in the epigenetic regulator MeCP2 that are associated with RTT lead to changes in enhancer activity in human stem cell models. Using state-of-the-art sequencing technologies, the student will profile chromatin structure and epigenetic marks during neural differentiation and identify regulatory mechanisms that drive RTT.

Project Description:

The human genome encodes hundreds of thousands of gene regulatory elements called enhancers. Enhancers are activated cell type-specifically to ensure that different cell types express a unique subset of active genes, thereby playing a central role in gene expression in human development and disease. Their dysregulation is increasingly implicated in neurodevelopmental disorders, but the mechanisms involved are poorly understood. The overall goal of this project is to address this gap. Rett syndrome (RTT) is a neurodevelopmental disorder characterised by impaired motor and cognitive function and autistic-like behaviours. It is caused by mutations in the gene encoding MeCP2, which is expressed at very high levels in neurons where it binds to epigenetic DNA
modifications present on enhancers. Recent models propose that MeCP2 mutations cause RTT by disrupting enhancer activity, highlighting the importance of studying the underlying mechanisms involved. Human-induced pluripotent stem cell (hiPSC) lines carrying specific mutations in MeCP2 provide a powerful model to study RTT, as they can be differentiated into neurons and compared to control cell lines with the same genetic background. The aim of this project is to use hiPSC models to understand how MeCP2 mutations disrupt enhancer activity
during neural differentiation. The objectives in Year 1 will be to: 1) identify the enhancers that are affected by MeCP2 mutations and 2) map changes in epigenetic modifications and chromatin structure at those enhancers. To do this the student will use cutting-edge genome sequencing technologies to identify enhancer-promoter pairs (with Dr. Sean Flynn) and to map epigenetic DNA modifications (with Dr. Jack Hardwick and Prof. Jonathan
Mill) during differentiation. The student will be trained in methods for profiling: (i) Accessible chromatin. Activation of enhancers is associated with an accessible, nucleosome-depleted chromatin state. (ii) Epigenetic marks. Changes in enhancer activity are associated with changes in histone and DNA modifications including H3K27ac, 5- methylcytosine and 5-hydroxymethylcytosine. (iii) DNA secondary structure. Although DNA usually exists as a double helix, enhancer elements often adopt a four-stranded DNA structure called a G-quadruplex. (iv) Enhancer-promoter contacts. Enhancers are often located long distances away from their target genes and are thought to be brought into contact by the 3D structure of the genome. The objective of Year 2 will be to integrate these genomic datasets to understand the order of events that occur during enhancer activation in normal differentiation, and how these are disrupted upon MeCP2 mutation. With support from each of the supervisors, the student will be trained in bioinformatics and data science, allowing them to interrogate and integrate the datasets generated during Year 1. This will allow the student to characterise the interplay between epigenetic features that regulate enhancers involved in RTT. The objective of Year 3 is to test whether chromatin and epigenetic changes identified by these analyses play a causal role in MeCP2- mediated disruption of enhancer function. The three supervisors will provide complementary expertise and support in functional genomics
approaches providing the student with an optimal environment to develop as an independent researcher – from developing a specific research question that interests them to devising and executing the experiments to address it. Depending on their interests, this may include using CRISPR methods for genome and epigenome editing and the use of reporter assays to measure enhancer function. Alternatively, the approach may employ brain organoids or the analysis of clinical data via collaboration with the NIHR Exeter BRC to test specific hypotheses in stem cell models derived from patients. Overall, this project will reveal important insights into neurodevelopment and provide the student with the freedom to develop into an independent scientist.

Funding

This studentship is funded through GW4BioMed2 MRC Doctoral Training Partnership. It consists of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£19,237 p.a. for 2024/25, updated each year).

Additional research training and support funding of up to £5,000 per annum is also available.

Eligibility

Residency:

The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Following Brexit, the UKRI now classifies EU students as international unless they have rights under the EU Settlement Scheme. The GW4 partners have agreed to cover the difference in costs between home and international tuition fees. This means that international candidates will not be expected to cover this cost and will be fully funded but need to be aware that they will be required to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD.  All studentships will be competitively awarded and there is a limit to the number of International students that we can accept into our programme (up to 30% cap across our partners per annum).

Academic criteria:

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences.  Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English requirements:

If English is not your first language you will need to meet the English language requirements of the university that will host your PhD by the start of the programme. Please refer to the details in the following web page for further information https://www.exeter.ac.uk/study/englishlanguagerequirements/

Data Protection

If you are applying for a place on a collaborative programme of doctoral training provided by Cardiff University and other universities, research organisations and/or partners please be aware that your personal data will be used and disclosed for the purposes set out below.

Your personal data will always be processed in accordance with the General Data Protection Regulations of 2018. Cardiff University (“University”) will remain a data controller for the personal data it holds, and other universities, research organisations and/or partners (“HEIs”) may also become data controllers for the relevant personal data they receive as a result of their participation in the collaborative programme of doctoral training (“Programme”).

Further Information

For an overview of the MRC GW4 BioMed programme please see the website www.gw4biomed.ac.uk

Entry requirements

Academic Requirements

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English Language Requirements

If English is not your first language you will need to meet the English language requirements of the university that will host your PhD by the start of the programme. Please refer to the relevant university website for further information.  This will be at least 6.5 in IELTS or an acceptable equivalent.  Please refer to the English Language requirements web page for further information.

How to apply

A list of all the projects and how to apply is available on the DTP’s website at gw4biomed.ac.uk.  You may apply for up to 2 projects and submit one application per candidate only.

Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’.  If successful, you will also need to make an application for an 'offer to study' to your chosen institution.

Please complete the online application form linked from our website by 5.00pm on Monday, 4th November 2024.  If you are shortlisted for interview, you will be notified from Friday, 20th December 2024.  Interviews will be held virtually on 23rd and 24th January 2025.

Further Information

For informal enquiries, please contact GW4BioMed@cardiff.ac.uk

For project related queries, please contact the respective supervisors listed on the project descriptions on our website.

Summary