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Dr Neil Thomson
Dr Sarah Harris
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
SUMMARY
The packing of DNA into a highly compacted state within the cell nucleus is an important factor in genetic control because it determines whether or not a gene can be expressed. Compaction of DNA involves processes that affect the super-coiling of the DNA double helix. We have devised a combined experimental and computational approach to investigate how super-coiling affects DNA recognition using topology dependent DNA-triplex formation and topology dependent DNA/protein recognition in small DNA circles. These model circles are sufficiently small to be amenable to molecular dynamics (MD) simulations, yet large enough for study by atomic force microscopy (AFM).
The project is cross-disciplinary with an experimental and theoretical supervisor. The project will encompass theoretical and experimental physics with biochemical approaches. The student will be trained in MD, molecular biology and AFM imaging.
OBJECTIVES: Small DNA circles (~100 to 200 basepairs) will be produced in a collaborators laboratory (Prof. Tony Maxwell, John Innes Centre, Norwich) and contain the required sequences and different levels of super-coiling. The student on the project will characterise the small DNA circles using atomic force microscopy in both imaging and nanomanipulation modes under supervision of Dr. Neil Thomson. In parallel, the student will compute the shapes of the circles and calculate binding free energy changes for comparison with the experimental data under the supervision of Dr. Sarah Harris and in collaboration with Prof. Charlie Laughton (Nottingham). This combination of physical techniques applied to molecular recognition within a model genome will provide new insight into genetic control, will benchmark the accuracy of computational models and provide new understanding of the mechanical properties of DNA and its complexes.
NOVELTY: The novelty arises from the use of the DNA mini circles with a size which allows a combined experimental/computational approach where outcomes can be compared directly. This will allow hypothesis driven research, where questions can be asked on how DNA supercoiling modulates the transcriptome in the context of a “model” genome in which the supercoiling is very well controlled.
TIMELINESS: Harris and Maxwell (JIC, Norwich) have a current BBSRC funding two postdoctoral researchers to work on this problem. The student on this project will be able to gain training and experience from both PDRAs within the first two years of their project. The Thomson group has recently achieved key advances in AFM technique that make the goals of the project attainable. Firstly, humidity controlled AFM can distinguish between supercoiled and un-supercoiled DNA molecules on the basis of induced conformational transitions. Secondly, a new imaging mode allows the helical pitch of the DNA to be resolved. Thirdly, nanomanipulation of DNA can also be used to ascertain the supercoiled state of the DNA.
The packing of DNA into a highly compacted state within the cell nucleus is an important factor in genetic control because it determines whether or not a gene can be expressed. Compaction of DNA involves processes that affect the super-coiling of the DNA double helix. We have devised a combined experimental and computational approach to investigate how super-coiling affects DNA recognition using topology dependent DNA-triplex formation and topology dependent DNA/protein recognition in small DNA circles. These model circles are sufficiently small to be amenable to molecular dynamics (MD) simulations, yet large enough for study by atomic force microscopy (AFM).
The project is cross-disciplinary with an experimental and theoretical supervisor. The project will encompass theoretical and experimental physics with biochemical approaches. The student will be trained in MD, molecular biology and AFM imaging.
OBJECTIVES: Small DNA circles (~100 to 200 basepairs) will be produced in a collaborators laboratory (Prof. Tony Maxwell, John Innes Centre, Norwich) and contain the required sequences and different levels of super-coiling. The student on the project will characterise the small DNA circles using atomic force microscopy in both imaging and nanomanipulation modes under supervision of Dr. Neil Thomson. In parallel, the student will compute the shapes of the circles and calculate binding free energy changes for comparison with the experimental data under the supervision of Dr. Sarah Harris and in collaboration with Prof. Charlie Laughton (Nottingham). This combination of physical techniques applied to molecular recognition within a model genome will provide new insight into genetic control, will benchmark the accuracy of computational models and provide new understanding of the mechanical properties of DNA and its complexes.
NOVELTY: The novelty arises from the use of the DNA mini circles with a size which allows a combined experimental/computational approach where outcomes can be compared directly. This will allow hypothesis driven research, where questions can be asked on how DNA supercoiling modulates the transcriptome in the context of a “model” genome in which the supercoiling is very well controlled.
TIMELINESS: Harris and Maxwell (JIC, Norwich) have a current BBSRC funding two postdoctoral researchers to work on this problem. The student on this project will be able to gain training and experience from both PDRAs within the first two years of their project. The Thomson group has recently achieved key advances in AFM technique that make the goals of the project attainable. Firstly, humidity controlled AFM can distinguish between supercoiled and un-supercoiled DNA molecules on the basis of induced conformational transitions. Secondly, a new imaging mode allows the helical pitch of the DNA to be resolved. Thirdly, nanomanipulation of DNA can also be used to ascertain the supercoiled state of the DNA.
Funding Notes
4 year BBSRC studentship, under the White Rose Mechanistic Biology DTP.
The successful applicant will receive fees and stipend (c.£13590 for 2013-14) and will start Oct 2013.Applicants should have, or be expecting to receive, a 2.1 Hons degree in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support.
There are 2 stages to the application process. Please see our website for more information:
http://www.fbs.leeds.ac.uk/gradschool/keywords/mnuFindaphd.php
In addition, there are other scholarships available at Leeds, including the University Research Scholarship competition which have closing dates from 20th January 2013 onwards.
The successful applicant will receive fees and stipend (c.£13590 for 2013-14) and will start Oct 2013.Applicants should have, or be expecting to receive, a 2.1 Hons degree in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support.
There are 2 stages to the application process. Please see our website for more information:
http://www.fbs.leeds.ac.uk/gradschool/keywords/mnuFindaphd.php
In addition, there are other scholarships available at Leeds, including the University Research Scholarship competition which have closing dates from 20th January 2013 onwards.
References
In the last 5 years, the Thomson group has published 23 papers, 18 of which included post-graduate authors, 15 as first author. Some selected publications (for full publication lists see http://www.astbury.leeds.ac.uk);
Billingsley D.J., Crampton N., Kirkham J., Thomson N.H., Bonass W.A (2012)
“Single-stranded loops as end-label polarity markers for double-stranded linear DNA templates in atomic force microscopy.” Nucleic Acids Research 40 (13) e99.
Billingsley D.J., Bonass W.A, Crampton N., Kirkham J. and Thomson N.H. (2012) “Single molecule studies of DNA transcription using atomic force microscopy.” Physical Biology 9, 021001
Billingsley D.J., Kirkham J., Bonass W.A, and Thomson N.H. (2010)
“Atomic force microscopy at high humidity: irreversible conformational switching of supercoiled DNA molecules.”
Phys. Chem. Chem. Phys. 12 (44), 14727 – 14734.
Crampton N., Bonass W.A., Kirkham J., Rivetti C. and Thomson N.H. (2006)
“Collision events between RNA polymerases in convergent transcription studied by atomic force microscopy.”
Nucleic Acids Research (2006) 34 (19) 5416-5425.
Mitchell J. S., Laughton C. A. & Harris S. A. “Atomistic simulations reveal kinks, bubbles and wrinkles in supercoiled DNA” (2011) Nucleic Acids Res. 39, 3928-3938.
Reha D., Voityuk A. & Harris S. A. “An in silico Design for a DNA Nanomechanical Switch” ACS Nano. (2010) 4, 5737-5742.
Rezac J., Hobza & Harris S. A. “Stretched DNA Investigated Using Molecular-Dynamics and Quantum-Mechanical Calculations” (2010) Biophys. J. 98, 101-110.
Harris S. A., Laughton C. A. & Liverpool T. B. “Mapping the phase diagram of the writhe of DNA nanocircles using atomistic molecular dynamics simulations” (2008) Nucleic. Acids. Res. 36, 21-29.
Billingsley D.J., Crampton N., Kirkham J., Thomson N.H., Bonass W.A (2012)
“Single-stranded loops as end-label polarity markers for double-stranded linear DNA templates in atomic force microscopy.” Nucleic Acids Research 40 (13) e99.
Billingsley D.J., Bonass W.A, Crampton N., Kirkham J. and Thomson N.H. (2012) “Single molecule studies of DNA transcription using atomic force microscopy.” Physical Biology 9, 021001
Billingsley D.J., Kirkham J., Bonass W.A, and Thomson N.H. (2010)
“Atomic force microscopy at high humidity: irreversible conformational switching of supercoiled DNA molecules.”
Phys. Chem. Chem. Phys. 12 (44), 14727 – 14734.
Crampton N., Bonass W.A., Kirkham J., Rivetti C. and Thomson N.H. (2006)
“Collision events between RNA polymerases in convergent transcription studied by atomic force microscopy.”
Nucleic Acids Research (2006) 34 (19) 5416-5425.
Mitchell J. S., Laughton C. A. & Harris S. A. “Atomistic simulations reveal kinks, bubbles and wrinkles in supercoiled DNA” (2011) Nucleic Acids Res. 39, 3928-3938.
Reha D., Voityuk A. & Harris S. A. “An in silico Design for a DNA Nanomechanical Switch” ACS Nano. (2010) 4, 5737-5742.
Rezac J., Hobza & Harris S. A. “Stretched DNA Investigated Using Molecular-Dynamics and Quantum-Mechanical Calculations” (2010) Biophys. J. 98, 101-110.
Harris S. A., Laughton C. A. & Liverpool T. B. “Mapping the phase diagram of the writhe of DNA nanocircles using atomistic molecular dynamics simulations” (2008) Nucleic. Acids. Res. 36, 21-29.
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Career overview
Dr Neil H Thomson joined the University of Leeds as an EPSRC Advanced Research Fellow in 2000 within the School of Physics and Astronomy. He obtained his PhD from the University of Bristol in 1995, followed by postdoctoral appointments at the University of California Santa Barbara (UCSB) from 1995 to 1997, the University of Nottingham in 1998, and the Ecole Polytechnique Federale de Lausanne (EPFL) in Switzerland in 1999. In 2005, he became a Leeds University Research Fellow, a position he held jointly between the Schools of Dentistry and Physics. Dr Thomson was promoted to Reader in Biological Physics and Bionanotechnology in 2010. His research expertise lies in atomic force microscopy (AFM) and its applications to study the structure and dynamics of biological systems at the molecular level. He jointly manages the Leeds AFM facility, which supports collaborative research across disciplines.
Research interests
Dr Thomson''s research focuses on atomic force microscopy (AFM) and its applications in studying the structure and dynamics of biological systems at the molecular level. His work aims to develop new AFM techniques and methods to enhance understanding of biological functions across various length scales, from nano to micro. Dr Thomson''s group employs AFM to image, measure forces, and manipulate materials ranging from biomolecules to macromolecular assemblies, cells, and tissues. He jointly manages the Leeds AFM facility, a multi-disciplinary research centre equipped with advanced AFM systems for collaborative research. Current projects in Dr Thomson''s group include: Investigating multiple RNA polymerase transactions on single DNA templates using simple in vitro gene models. Developing DNA nanostructures for biomedical applications. Examining the nanomechanical response of hydrogels for regenerative medicine. Studying the mechanical behaviour of engineered therapeutic microbubbles. Advancing AFM methods for applications in soft matter and biomaterial systems.
Bionanotechnology
Biological Physics
Atomic Force Microscopy
DNA-Protein Interactions
DNA Nanotechnology
Hydrogels
Microbubbles
Molecular Resolution
Biomolecular Systems
Mechanical Properties
Nanomechanical Response
Regenerative Medicine
Biomedical Applications
Soft Matter
Biomaterial Systems
Integrated MSc and PhD in Oral Sciences.
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