Topology, structures, and energy landscapes of human chromosomes

Significance Various cell types emerge from their nearly identical genetic content for a multicellular organism, in part, via the regulation of the function of the genome—the DNA molecules inside the cell. Similar to the way catalytic activity is lost when proteins denature, the function of the genome is tightly coupled to its 3D organization. A theoretical framework for picturing the structure and dynamics of the genome will therefore greatly advance our understanding of cell biology. We present an energy landscape model of the chromosome that reproduces a diverse set of experimental measurements. The model enables quantitative predictions of chromosome structure and topology and provides mechanistic insight into the role of 3D genome organization in gene regulation and cell differentiation. Chromosome conformation capture experiments provide a rich set of data concerning the spatial organization of the genome. We use these data along with a maximum entropy approach to derive a least-biased effective energy landscape for the chromosome. Simulations of the ensemble of chromosome conformations based on the resulting information theoretic landscape not only accurately reproduce experimental contact probabilities, but also provide a picture of chromosome dynamics and topology. The topology of the simulated chromosomes is probed by computing the distribution of their knot invariants. The simulated chromosome structures are largely free of knots. Topologically associating domains are shown to be crucial for establishing these knotless structures. The simulated chromosome conformations exhibit a tendency to form fibril-like structures like those observed via light microscopy. The topologically associating domains of the interphase chromosome exhibit multistability with varying liquid crystalline ordering that may allow discrete unfolding events and the landscape is locally funneled toward “ideal” chromosome structures that represent hierarchical fibrils of fibrils.