How does non-coding RNA structure regulate gene expression?

Background:

Long non-coding RNAs (lncRNAs) play a vital role in human physiology through regulating gene expression, impacting fundamental cellular processes. Dysregulation and mutations in lncRNAs are associated with cancer formation, neurodegeneration and cardiovascular disease. However we still do not fully understand how they function and cause these diseases.

lncRNAs fold into complex and dynamic structures, but the structural basis for their function remains poorly understood. In this project you will use cutting-edge single-molecule approaches to measure the structure of individual RNA molecules. We will use the HOTAIR lncRNA as a model (which has a well characterised secondary structure and defined binding partners), and deconvolute distinct conformational states to investigate the role of RNA structures in lncRNA function. 

Objectives:

1. Use single-molecule optical-tweezers and AFM to determine the structural conformations of the HOTAIR lncRNA 
2. Generate and characterise recombinant chromatin remodelling proteins known to interact with HOTAIR
3. Investigate how HOTAIR RNA structure effects the interaction and activity of these proteins 

Approach:

Conventional methods of studying lncRNA structure only report an average of the many possible conformations. Using single-molecule approaches of optical-tweezer and AFM we will identify and characterise specific conformational states. 

The full HOTAIR lncRNA, and individual domains, will be tethered in optical-tweezers assays allowing sub-pN force manipulation and measurements. This will allow us unprecedented insight into the conformation and stability of the RNA secondary structure. Using the complementary approach of high-resolution AFM we will obtain structures of individual molecules. 

HOTAIR is known to interact with the chromatin modifying protein complexes to regulate gene expression. These will be generated recombinantly and their interactions and activity with HOTAIR characterised using biochemical and single-molecule biophysics assays. Together this will enable us to understand the structural basis of HOTAIR lncRNA activity in regulation of gene expression through interaction with chromatin modifying enzymes. The project will provide exciting and novel insights into the mechanism of lncRNAs.

Apply:

Interested candidates are strongly encouraged to contact the project supervisors to discuss your interest in and suitability for the project prior to submitting your application. For any queries about the project please contact Dr Matt Newton [email protected].

About YBDTP:

YBDTP brings together world-class bioscience research and innovation, as well as excellence in doctoral supervision, across the region. YBDTP will fund postgraduate researchers at the Universities of Leeds, Sheffield, York, Bradford, Hull, Leeds Beckett, Sheffield Hallam and Teesside forming a strong regional training partnership. In YBDTP you’ll benefit from a regional doctoral training programme that has interdisciplinary collaboration at its core. The aim is to enable you to develop a range of research skills in biological, biotechnology and biochemical areas as well as equip you with core data analysis and professional skills that are necessary for bioscience research and related non-academic careers.

https://www.whiterose-mechanisticbiology-dtp.ac.uk/yorkshire-bioscience-dtp/

Funding Notes:

Funding: A tax-free annual stipend at the standard UKRI rate (£19,237 for 2024/25 entry), research costs and tuition fees at UK rate

Academic year: 2025/26

Open to: International (including EU) and UK (home) students

Eligibility:

Open to International (including EU) and UK (home) students.

You can apply if you have, or are expecting to gain, at least an upper second-class honours degree or equivalent. Due to the interdisciplinary nature of this programme, we welcome applications if your background is in any biological, chemical or physical science or mathematics and are interested in using your skills in addressing biological questions. International students should check if they meet the entry requirements for their country.

We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international (EU and non-EU) applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. 

The Yorkshire Bioscience DTP is committed to recruiting extraordinary future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation or career pathway to date. We understand that commitment and excellence can be shown in many ways and have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.

English language:

If English isn’t your first language, you may need to provide evidence of your English language ability.

How to apply:

Application deadline: 5pm, Friday 14^th March 2025

To submit your application, click on the link to the Expression of Interest form in the Funding Notes section of any of your chosen projects. You can apply for up to 3 YBDTP projects (which can be at different universities).

We would advise you to read the questions in the form before submitting your application. Inside the form there is a link to a document for you to see the questions in advance.

If you have any questions about the application process, please email [email protected].

If you have any questions about the project you are interested in, please email the project supervisor (details inside the project description).

How we allocate:

Shortlisting will take place as soon as possible after the closing date and successful applicants will be notified promptly. If you’re shortlisted, you’ll be invited for an interview on a date to be confirmed in February 2025. You’ll be notified as soon as possible after the interview dates whether your application has been successful, placed on a reserve list or unsuccessful. If you are successful, you’ll be required to confirm your intention to accept the studentship within 10 days.

Terms and conditions:

The studentships are fully funded for four years, and you must complete your PhD in four years.

You’ll receive the UKRI minimum doctoral stipend per year for your living costs, which is paid to you in regular instalments. The UK Research and Innovation (UKRI) stipend is tax free and does not need to be paid back.

International students will need to have sufficient funds to cover the costs of their student visa, NHS health surcharge, travel insurance and travel to the UK as these are excluded from UKRI funding.