Euchromatin Activity Enhances Segregation and Compaction of Heterochromatin in the Cell Nucleus
Year: 2022
Type: article
Abstract: The large-scale organization of the genome inside the cell nucleus is critical for the cell’s function. Chromatin – the functional form of DNA in cells – serves as a substrate for active nuclear processes such as transcription, replication and DNA repair. Chromatin’s spatial organization directly affects its accessibility by ATP-powered enzymes, e.g., RNA polymerase II in the case of transcription. In differentiated cells, chromatin is spatially segregated into compartments – euchromatin and heterochromatin – the former being largely transcriptionally active and loosely packed, the latter containing mostly silent genes and densely compacted. The euchromatin/heterochromatin segregation is crucial for proper genomic function, yet the physical principles behind it are far from understood. Here, we model the nucleus as filled with hydrodynamically interacting active Zimm chains – chromosomes – and investigate how large heterochromatic regions form and segregate from euchromatin through their complex interactions. Each chromosome presents a block copolymer composed of heterochromatic blocks, capable of crosslinking that increases chromatin’s local compaction, and euchromatic blocks, subjected to stochastic force dipoles that capture the microscopic stresses exerted by nuclear ATPases. These active stresses lead to a dynamic self-organization of the genome, with its coherent motions driving the mixing of chromosome territories as well as large-scale heterochromatic segregation through crosslinking of distant genomic regions. We study the stresses and flows that arise in the nucleus during the heterochromatic segregation, and identify their signatures in Hi-C proximity maps. Our results reveal the fundamental role of active mechanical processes and hydrodynamic interactions in the kinetics of chromatin compartmentalization and in the emergent large-scale organization of the nucleus.
Source: Physical Review X
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,200
Awards: G1410324694, Collaborative Research: DMS/NIGMS2: Discovering the Principles of Active Self-Organization in the Differentiating Genome Using Multi-Scale Modeling and In-Vivo Experiments, Investigating Phase Separations as a Mechanism of Genome Compartmentalization Through In-vivo Experiments, G2503993218, G254687084, Collaborative Research: Interphase Chromatin as a Complex Active Fluid: Experiments and Microscopic to Mesoscopic Modeling, Collaborative Research: DMS/NIGMS2: Discovering the Principles of Active Self-Organization in the Differentiating Genome Using Multi-Scale Modeling and In-Vivo Experiments, G3387330441, G47664111, G6671297155, CAREER: Physics of Chromatin: Micromechanics of Active Chromatin Dynamics in Interphase, Collaborative Research: Multiscale engineering of active stress in biomaterials, G7805964360, Collaborative Research: Interphase Chromatin as a Complex Active Fluid: Experiments and Microscopic to Mesoscopic Modeling
OpenAlex ID: W4312180444