PhD project: Physics of genome structure in health and disease
Project description
The genome is the genetic material of an organism. Consisting of DNA packaged up with proteins to form chromosomes, it contains the instruction set or genetic code which tells a cell how to grow and function. The genome must be copied when cells grow and divide, and must be accessed to read the code to produce proteins, the building blocks of the cell. In different types of cell and during different stages of development, different parts of the genetic code need to be accessed, i.e. different genes need to be switched on or off. The physical polymer structure of the chromosomes plays a major role in how this is regulated. We are interested in using computer simulations and methods from soft matter and statistical physics to understand this in healthy cells and disease.
Possible projects include:
- Using polymer simulations to understand how genome rearrangements lead to mis-regulation of genes in genetic disorders and cancer. You will use and further develop an existing simulation model which can predict chromosome loops which drive gene expression. Using data from collaborators at the University of Newcastle, you will use the simulations to predict how genome rearrangements found in cancer change this looping structure. Genome rearrangements can occur, for example, when breaks in the chromosomes are incorrectly repaired, and regions which are usually far apart in the genome are brought together. This results in changes to the chromatin polymer structure; you will use non-equilibrium polymer models to simulate this process. The simulation results will help us understand how common rearrangements give rise to disease, and will help our experimental collaborators with development of possible treatments.
- Modelling chromatin structure at the short length scale to understand its properties at larger scales. Chromatin is the composite material made up from DNA and proteins which forms the chromosomes. A nucleosome is a disk-like structure formed when DNA wraps around a bundle of proteins called histones; a chain of nucleosomes forms a chromatin fibre. Though the crystal structure of the nucleosome is known, how a chain of nucleosomes folds up, and how that affects the larger scale polymer structure is still unclear. The picture is complicated by the fact that the proteins making up the nucleosomes can be chemically modified, and this changes how different nucleosomes interact, and stably wrapped the DNA is. Recent developments in experimental methods have provided new data on the positions and interactions of nucleosomes around gene regulation regions on the chromosomes. In this project you will use coarse grained molecular dynamics simulations and further develop models for chromatin fibres to make use of this data. You will then use the model to understand how changes in nucleosome positions, e.g. when genes are activated, change the larger scale structure. There will be opportunities to work with experimental data from collaborators.
Some relevant references:
- Daniel Rico, Daniel Kent, Aneta Mikulasova, Nefeli Karataraki, Rolando Berlinguer-Palmini, Brian A. Walker, Biola M. Javierre, Lisa J. Russell, Chris A. Brackley "High-resolution simulations of chromatin folding at genomic rearrangements in malignant B-cells provide mechanistic insights on proto-oncogene deregulation" Genome Research 32 1355-1366 (2022) link
- O. Wiese, D. Marenduzzo, and C. A. Brackley "Nucleosome positions alone determine micro-domains in yeast chromosomes" Proc. Natl. Acad. Sci. USA 116 17307-17315 (2019) link
- G. Forte, A. Buckle, S. Boyle, D. Marenduzzo, N. Gilbert, and C. A. Brackley "Transcription modulates chromatin dynamics and locus configuration sampling" Nature Structural & Molecular Biology 30 1275–1285 (2023) link
- A. Buckle, C. A. Brackley, S. Boyle, D. Marenduzzo and N. Gilbert "Polymer Simulations of Heteromorphic Chromatin Predict the 3-D Folding of Complex Genomic Loci" Molecular Cell 72 1-12 (2018) link
Project supervisor
- Dr Chris Brackley (School of Physics & Astronomy, University of Edinburgh)
The project supervisor welcomes informal enquiries about this project.
Find out more about this research area
The links below summarise our research in the area(s) relevant to this project:
- Find out more about Physics of Living Matter.
- Find out more about the Institute for Condensed Matter and Complex Systems.
What next?
- Find out how to apply for our PhD degrees.
- Find out about fees and funding and studentship opportunities.
- View and complete the application form (on the main University website).
- Find out how to contact us for more information.