How enzymatic activity is involved in chromatin organization

  1. Rakesh Das  Is a corresponding author
  2. Takahiro Sakaue
  3. G V Shivashankar
  4. Jacques Prost
  5. Tetsuya Hiraiwa  Is a corresponding author
  1. National University of Singapore, Singapore
  2. Aoyama Gakuin University, Japan
  3. ETH Zurich, Switzerland
  4. Institute Curie, France

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

  1. Rakesh Das

    National University of Singapore, Singapore, Singapore
    For correspondence
    rakeshd68@yahoo.com
    Competing interests
    The authors declare that no competing interests exist.
  2. Takahiro Sakaue

    Department of Physics and Mathematics, Aoyama Gakuin University, Sagamihara, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0863-6682
  3. G V Shivashankar

    ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Jacques Prost

    Laboratoire Physico Chimie Curie, Institute Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Tetsuya Hiraiwa

    National University of Singapore, Singapore, Singapore
    For correspondence
    mbithi@nus.edu.sg
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "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

© 2022, Das et al.

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.

Metrics

  • 1,381
    views
  • 255
    downloads
  • 13
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Rakesh Das
  2. Takahiro Sakaue
  3. G V Shivashankar
  4. Jacques Prost
  5. Tetsuya Hiraiwa
(2022)
How enzymatic activity is involved in chromatin organization
eLife 11:e79901.
https://doi.org/10.7554/eLife.79901

Share this article

https://doi.org/10.7554/eLife.79901

Further reading

    1. Computational and Systems Biology
    2. Physics of Living Systems
    Ju Kang, Shijie Zhang ... Xin Wang
    Research Article

    Explaining biodiversity is a fundamental issue in ecology. A long-standing puzzle lies in the paradox of the plankton: many species of plankton feeding on a limited variety of resources coexist, apparently flouting the competitive exclusion principle (CEP), which holds that the number of predator (consumer) species cannot exceed that of the resources at a steady state. Here, we present a mechanistic model and demonstrate that intraspecific interference among the consumers enables a plethora of consumer species to coexist at constant population densities with only one or a handful of resource species. This facilitated biodiversity is resistant to stochasticity, either with the stochastic simulation algorithm or individual-based modeling. Our model naturally explains the classical experiments that invalidate the CEP, quantitatively illustrates the universal S-shaped pattern of the rank-abundance curves across a wide range of ecological communities, and can be broadly used to resolve the mystery of biodiversity in many natural ecosystems.

    1. Computational and Systems Biology
    2. Physics of Living Systems
    Divyoj Singh, Sriram Ramaswamy ... Mohd Suhail Rizvi
    Research Article

    Planar cell polarity (PCP) – tissue-scale alignment of the direction of asymmetric localization of proteins at the cell-cell interface – is essential for embryonic development and physiological functions. Abnormalities in PCP can result in developmental imperfections, including neural tube closure defects and misaligned hair follicles. Decoding the mechanisms responsible for PCP establishment and maintenance remains a fundamental open question. While the roles of various molecules – broadly classified into “global” and “local” modules – have been well-studied, their necessity and sufficiency in explaining PCP and connecting their perturbations to experimentally observed patterns have not been examined. Here, we develop a minimal model that captures the proposed features of PCP establishment – a global tissue-level gradient and local asymmetric distribution of protein complexes. The proposed model suggests that while polarity can emerge without a gradient, the gradient not only acts as a global cue but also increases the robustness of PCP against stochastic perturbations. We also recapitulated and quantified the experimentally observed features of swirling patterns and domineering non-autonomy, using only three free model parameters - the rate of protein binding to membrane, the concentration of PCP proteins, and the gradient steepness. We explain how self-stabilizing asymmetric protein localizations in the presence of tissue-level gradient can lead to robust PCP patterns and reveal minimal design principles for a polarized system.