Unravelling Genome Structure and Function through Experimentally Informed Polymer Models

Abstract

The genome is the primary information storage system of the cell. However, it is not fully established how eukaryotic and prokaryotic genomes are organized and function within cells. To fill this gap I used experimentally informed polymer models to reconstruct the 3D structures of the Schizosaccharomyces pombe and Escherichia coli genomes. I generated 3D models of the E. coli chromosome that were non-specifically compressed within cells. These models have shown that at the scales of several kb the E. coli chromosome organization cannot be described as random chromosome packing, while at scales starting from several tens of kb the E. coli chromosome is highly mixed and entangled. The polymer models of the S. pombe genome provided evidence that chromosomal interactions, detected by conformation capture experiments, play a structural role in S. pombe genome organization. I used ensembles of the S. pombe genome structures to construct 3D maps of genes, epigenetic marks, and replication origins. The 3D maps demonstrated that the S. pombe genome is highly compartmentalized. I found that highly transcribed genes and active epigenetic marks (H3K4me) are preferentially located toward the S. pombe nuclear interior, and inactive epigenetic mark (H3K9me) towards the nuclear periphery. The 3D maps of genetic elements that I generated represent a significant step towards the development of unified models for spatial gene regulation, DNA repair and replication.