Chromosome-wide simulations uncover folding pathway and 3D organization of interphase chromosomes

TL;DR

This study uses chromosome-wide simulations to reveal the folding pathway and 3D organization of interphase chromosomes, highlighting the role of Polycomb complexes in TAD formation and chromosome architecture.

Contribution

It introduces a simulation-based model that predicts 3D chromosome organization and folding dynamics, integrating chromatin factors and revealing a two-step formation process.

Findings

Polycomb-repressive-complex-1 predicts a subset of TADs.

All TADs are recapitulated with additional factors.

Chromosome 3R organization forms via a two-step process.

Abstract

Three-dimensional interphase organization of metazoan genomes has been linked to cellular identity. However, the principles governing 3D interphase genome architecture and its faithful transmission through disruptive events of cell-cycle, like mitosis, are not fully understood. By using Brownian dynamics simulations of Drosophila chromosome 3R up to time-scales of minutes, we show that chromatin binding profile of Polycomb-repressive-complex-1 robustly predicts a sub-set of topologically associated domains (TADs), and inclusion of other factors recapitulates the profile of all TADs, as observed experimentally. Our simulations show that chromosome 3R attains interphase organization from mitotic state by a two-step process in which formation of local TADs is followed by long-range interactions. Our model also explains statistical features and tracks the assembly kinetics of polycomb subnuclear clusters. In conclusion, our approach can be used to predict structural and kinetic features of 3D chromosome folding and its associated proteins in biological relevant genomic and time scales.