Physics plays part in predicting cancer

Polymer physics modelling predicts interactions in cancer genomes.

An interdisciplinary team of physicists and biologists, including Dr Chris Brackley from the Institute for Condensed Matter and Complex Systems at the University of Edinburgh, and Dr Lisa Russel and Dr Daniel Rico from Newcastle University, used polymer physics based simulations to make predictions of the three-dimensional organisation of chromosomes near to sites of incorrect repair.

Their model predicts which enhancer sites will contact the genes in different cancer cells. The lab-based team can then perform experiments where these sites are targeted, with the aim of reversing the disease state. Not only are the simulations a useful tool for helping direct the experiments, but they also give important insight into the biological and physical processes which lead to the loops forming.

Gene regulation

The chromosomes in our cell nuclei are long fibres made up from DNA and proteins. One mechanism through which genes are regulated is via changes in the three-dimensional organisation of the chromosomes. For example, often, to activate a gene, sites on the chromosome called ‘enhancers’ have to be brought into physical contact with the gene, folding the chromosome into a loop.

Many cancers arise when the chromosomes are broken, and then incorrectly repaired. For example, the broken ends of two different chromosomes can become joined together; genes near to the join can find themselves in contact with enhancers they would not normally encounter. This leads to chemical modification of the chromosome near these genes (chemical ‘marks’ known as H3K4 tri-methylation, or H3K4me3 are deposited). These ‘oncogenes’ then become constantly active, promoting continuous cell division and cancer.

Dr Lisa Russel, Cancer Biologist at Newcastle University said:

Not only do the simulations allow us to understand how the H3K4me3 domains translocate, but they suggest sites on the DNA which can then betargeted in experiments that aim to reverse the disease.

Published work

The work is part of a set of three papers from the same groups of authors which feature of the cover of the July 2022 edition of Genome Research. Together, these works show that H3K4me3 broad domains are associated with regulatory elements of cell identity genes, called super-enhancers, that are ‘hijacked’ to interact with other genes in cancer cells; this is associated with the disappearance of the H3K4me3  domains from cell identity genes, and their appearance over oncogenes. The work showed that the regulation of H3K4me3 broad domains is associated with leukemogenesis and suggests that the presence of these structures might be used for epigenetic prioritisation of cancer-relevant genes.

Science–art collaboration

The teams also worked together with multimedia science artist Dr Dimple Devadas, who produced a series of artworks inspired by the projects. One of the artworks was used on the journal cover, and the others appear in an online exhibition Science as Genome art, showcasing this coming together of cancer biology, polymer physics, and art.