The spatial organisation of the chromosomes in cell nuclei is intimately linked to gene regulation, and in turn cell function and identity. For example, repressed regions of the genome tend to be more compacted (and inaccessible to the transcriptional material), while expression of genes in active regions of the genome often requires formation of chromatin loops. Patterns of activation and repression change through cell development and are different in different types of cell. Diseases such as cancer can arise when incorrect repair of DNA breakages regulates in genome rearrangements which disrupt this 3D organisation.
I will present a polymer physics-based simulation scheme which can predict the 3D structure of the genome based on protein binding and chromatin modification data [1]. This model incorporates several physical mechanisms which drive the polymer (representing chromatin - the fibrous material which makes up our chromosomes) into specific configurations. These include a "bridging-induced attraction mechanism", where chromatin-protein-chromatin bridging interactions drive formation of protein clusters [2,3], and a loop extrusion mechanism, where the polymer is activity pushed into loops [4]. I will discuss some of the underlying physics, before briefly showing some recent results from simulations of cancer genomes.
[1] 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" Mol Cell 72 1-12 (2018)
[2] C. A. Brackley, S. Taylor, A. Papantonis , P. R. Cook, and D. Marenduzzo "Nonspecific bridging-induced attraction drives clustering of DNA-binding proteins and genome organization" Proc. Natl. Acad. Sci. USA 110 E3605 (2013)
[3] C. A. Brackley "Polymer compaction and bridging-induced clustering of protein-inspired patchy particles" J Phys Condens Matt 32 314002 (2020)
[4] G. Fudenberg, M. Imakaev, C. Lu, A. Goloborodko, N. Abdennur, L.A. Mirny "Formation of Chromosomal Domains by Loop Extrusion" Cell Rep 15 2038-2049 (2016)