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Atomic force microscopy studies of the molecular mechanisms of nested genes related to tooth formation

PGR-P-223

Key facts

Type of research degree
PhD
Application deadline
Ongoing deadline
Country eligibility
International (open to all nationalities, including the UK)
Funding
Non-funded
Supervisors
Dr Georg Feichtinger
Schools
School of Dentistry
<h2 class="heading hide-accessible">Summary</h2>

Transcription is the molecular process in the cell whereby the genetic information from DNA is copied into messenger RNA by the molecular motor RNA polymerase (RNAP) which catalyses the polymerisation of ribonucleotides. Since DNA is a helical molecule, the RNAP needs to rotate relative to the DNA template to undergo transcription. On a torsionally constrained template, the RNAP will therefore cause over-winding of the DNA in front of it and under-wound DNA behind, as it translocates along the DNA. This effect is known as the twin supercoiling domain hypothesis and it is expected that build-up of localised supercoiling within the DNA will affect the ability of the RNAP to copy the gene in question: it is therefore a fundamental physical mechanism that modulates gene expression.

<h2 class="heading hide-accessible">Full description</h2>

<p>We investigate this question through constructed systems in vitro using high resolution imaging of individual molecular complexes using atomic force microscopy (AFM). The translocation of DNA through RNAP as transcription occurs in vitro was first followed using atomic force microscopy (AFM) at the single molecule level and more recently, we have been investigating the interactions of more than one RNAP on a single DNA template. Interestingly, we find that the position of one RNAP during transcription is influenced by another RNAP operating at the same time. Currently, it seems that this effect occurs regardless of whether these RNAPs are travelling towards each other or in the same direction. This project will continue our investigations into the fundamental mechanisms involved in spatial regulation of the RNAPs. Our working hypothesis is that local supercoiling of the DNA between RNAPs causes them to stall or pause when they get too close to one another. This may be one fundamental way that the cell controls gene expression through the physical properties of the DNA, but more work is needed to prove the hypothesis and understand the details.</p> <p>It is being increasingly discovered that many genes lie in a nested formation, such that the promoters are convergently aligned on opposite DNA strands in the double helix. The implications for simultaneous expression of these genes are obvious and lead one to ask what would occur if two RNAP encounter each other on a single template. We propose to investigate a nested gene system involved in tooth enamel development where the expression of the biomineralising amelogenin protein may be compromised. The outcomes of this project will help to inform us about fundamental aspects of developmental biology and have long term impact on the treatment of diseased states associated with altered gene expression.</p>

<h2 class="heading">How to apply</h2>

<p>Applications can be made at any time. To apply for this project applicants should complete a<a href="https://medicinehealth.leeds.ac.uk/downloads/download/129/faculty_graduate_school_-_application_form"> Faculty Application Form</a> and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>.</p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>If you have already applied for other projects using the Faculty Application Form this academic session you do not need to complete this form again. Instead you should email&nbsp;<a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a> to inform us you would like to be considered for this project.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <p><em>We welcome applications from all suitably-qualified candidates, but UK black and minority ethnic (BME) researchers are currently under-represented in our Postgraduate Research community, and we would therefore particularly encourage applications from UK BME candidates. All scholarships will be awarded on the basis of merit.</em></p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &acirc;&euro;&cent; British Council IELTS - score of 6.5 overall, with no element less than 6.0 &acirc;&euro;&cent; TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

<h2 class="heading">Contact details</h2>

<p>For further information please contact the Graduate School Office<br /> e: <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>, t: +44 (0)113 343 8221.</p>