A Hi–C data-integrated model elucidatesE. colichromosome’s multiscale organization at various replication stages

Abstract

The chromosome of Escherichia coli is riddled with multi-faceted complexity. The emergence of chromosome conformation capture techniques are providing newer ways to explore chromosome organization. Here we combine a beads-on-a-spring polymer-based framework with recently reported Hi–C data for E. coli chromosome, in rich growth condition, to develop a comprehensive model of its chromosome at 5 kb resolution. The investigation focuses on a range of diverse chromosome architectures of E. coli at various replication states corresponding to a collection of cells, individually present in different stages of cell cycle. The Hi–C data-integrated model captures the self-organization of E. coli chromosome into multiple macrodomains within a ring-like architecture. The model demonstrates that the position of oriC is dependent on architecture and replication state of chromosomes. The distance profiles extracted from the model reconcile fluorescence microscopy and DNA-recombination assay experiments. Investigations into writhe of the chromosome model reveal that it adopts helix-like conformation with no net chirality, earlier hypothesized in experiments. A genome-wide radius of gyration map captures multiple chromosomal interaction domains and identifies the precise locations of rrn operons in the chromosome. We show that a model devoid of Hi–C encoded information would fail to recapitulate most genomic features unique to E. coli.

Hi-C Contacts Encode Heterogeneity in Sub-diffusive Motion of E. coli Chromosomal Loci

“…Towards this end, we implemented a computer model of the E. coli chromosome by integrating beads-spring polymer topology with recently reported Hi-C interactions matrix of E. coli [13] chromosome at this particular condition (wt30MM). For this purpose, we employ a recently proposed protocol by our group [14]. As detailed in the Simulation Model and Methods section, the excluded volume interaction, Hi-C contacts and a spherocylindrical confinement form the key interactions of the model.…”

“…Here we are interested in short-time chromosomal loci dynamics in minimal medium (wt30MM), i.e there is only one single chromosome and no replication fork. We model the E. coli chromosome as a bead-spring polymer chain, with each bead representing 5 × 10 3 bp (5 kb), the same as our previous work [14]. This resolution is also the same as Hi-C interaction maps reported by Lioy et al [13].…”

“…This relation implies that the force constanta becomes smaller for larger distances and the k 0 value is the upper bound of the force constant. We have used a value of k 0 = 10 [14]. For optimization of w we have calculated the Pearson Correlation coefficient between the experimental and simulated contact probability matrices with varying w 2 .…”

“…In particular, a high resolution (5kb), Hi-C contact map for E. coli has recently been reported by Lioy et al [13]. The subsequent integration of this Hi-C interaction map in a polymer-based computational model [14], had bestowed a clear chromosomal compartmentalization, a fundamental building block of E. coli chromosomal architecture. In light of this, the center of our current investigation is: how does the self-organized nature of the E. coli chromosome impact the dynamics of its individual loci?…”

“…Based on these precedent investigations and particularly the observation of the heterogeneous diffusivity across the loci, we surmised that the inter-loci cross-talk and specific identity of loci pair might play an important role. Towards this end, we planned on employing our recent model of E. coli chromosome [14], which had integrated the high-resolution (5 kb) Hi-C interaction map [13] in an excluded-volume polymer-based framework, for investigating the dynamics of the chromosomal loci. Specifically we use this Hi-C-encoded model to explore the mobility of each of 30 loci (same set of loci as investigated by Javer et al's tracking experiments) via Brownian Dynamics (BD) simulations.…”