How enzymatic activity is involved in chromatin organization

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Abstract

Spatial organization of chromatin plays a critical role in genome regulation. Previously, various types of affnity mediators and enzymes have been attributed to regulate spatial organization of chromatin from a thermodynamics perspective. However, at the mechanistic level, enzymes act in their unique ways and perturb the chromatin. Here, we construct a polymer physics model following the mechanistic scheme of Topoisomerase-II, an enzyme resolving topological constraints of chromatin, and investigate how it affects interphase chromatin organization. Our computer simulations demonstrate Topoisomerase-II's ability to phase separate chromatin into eu- and heterochromatic regions with a characteristic wall-like organization of the euchromatic regions. We realized that the ability of the euchromatic regions to cross each other due to enzymatic activity of Topoisomerase-II induces this phase separation. This realization is based on the physical fact that partial absence of self-avoiding interaction can induce phase separation of a system into its self-avoiding and non-self-avoiding parts, which we reveal using a mean-field argument. Furthermore, motivated from recent experimental observations, we extend our model to a bidisperse setting and show that the characteristic features of the enzymatic activity driven phase separation survive there. The existence of these robust characteristic features, even under the non-localized action of the enzyme, highlights the critical role of enzymatic activity in chromatin organization.

Data availability

All data generated or analysed are included in the manuscript. Two source codes used to simulate all the variants of models presented here are shared as supplemental files -Source code 1: CPU-based FORTRAN simulation code using OpenMP API. Instructions to use this can be found in the README text accompanying the source code.Source code 2: CUDA FORTRAN simulation code using GPU acceleration. Instructions to use this can be found in the README text accompanying the source code.

Article and author information

Author details

Rakesh Das

National University of Singapore, Singapore, Singapore

For correspondence
rakeshd68@yahoo.com

Competing interests
The authors declare that no competing interests exist.
Takahiro Sakaue

Department of Physics and Mathematics, Aoyama Gakuin University, Sagamihara, Japan

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0863-6682
G V Shivashankar

ETH Zurich, Zurich, Switzerland

Competing interests
The authors declare that no competing interests exist.
Jacques Prost

Laboratoire Physico Chimie Curie, Institute Curie, Paris, France

Competing interests
The authors declare that no competing interests exist.
Tetsuya Hiraiwa

National University of Singapore, Singapore, Singapore

For correspondence
mbithi@nus.edu.sg

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3221-345X

Funding

Mechanobiology Institute, Singapore (Seed grand)

Jacques Prost
Tetsuya Hiraiwa

Ministry of Education - Singapore (Tier 3 grant MOET32020-0001)

G V Shivashankar
Jacques Prost
Tetsuya Hiraiwa

Japan Society for the Promotion of Science (KAKENHI JP18H05529)

Takahiro Sakaue

Ministry of Education, Culture, Sports, Science and Technology (JP21H05759)

Takahiro Sakaue

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.