How enzymatic activity is involved in chromatin organization

Abstract

Spatial organization of chromatin plays a critical role in genome regulation. Various types of affinity 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. Here, we construct a polymer physics model following the mechanistic scheme of Topoisomerase-II, an enzyme resolving topological constraints of chromatin, and investigate its role on interphase chromatin organization. Our computer simulations demonstrate Topoisomerase-II's ability to phase separate chromatin into eu-and heterochromatic regions with a characteristic walllike organization of the euchromatic regions. Exploiting a mean-field framework, we argue that the ability of the euchromatic regions crossing each other due to enzymatic activity of Topoisomerase-II induces this phase separation. Motivated from a recent experimental observation on different structural states of the eu-and the heterochromatic units, we further extend our model to a bidisperse setting and show that the characteristic features of the enzymatic activity driven phase separation survives there. The existence of these characteristic features, even under the non-localized action of the enzyme, highlights the critical role of enzymatic activity in chromatin organization, and points out the importance of further experiments along this line.

Polymeric nature of tandemly repeated genes enhances assembly of constitutive heterochromatin in fission yeast

“…It is very different from other theories of heterochromatin assembly, which are based on the theory of phase separation(Cook and Marenduzzo 2009, Brackley et al 2013, Ganai et al 2014, Jerabek and Heerman 2014, Awazu 2015, Yamamoto and Schiessel 2016, 2017a, 2017b, Michieletto et al 2019, Falk et al 2019, Adachi and Kawaguchi 2019, Das et al 2021, Fujishiro and Sasai 2022.…”

“…Biophysically, heterochromatin has been thought to be assembled by the phase separation of chromatin (Cook and Marenduzzo 2009, Brackley et al 2013, Ganai et al 2014, Jerabek and Heerman 2014, Awazu 2015, Yamamoto and Schiessel 2016, 2017a, 2017b, Michieletto et al 2019, Falk et al 2019, Adachi and Kawaguchi 2019, Das et al 2021, Fujishiro and Sasai 2022. The constitutive heterochromatin is characterized by the post-translational modification of histone tails, H3K9me2/3, of nucleosomes.…”

Active Transcription and Epigenetic Reactions Synergistically Regulate Meso-Scale Genomic Organization

“…While on one hand, spatial organization of chromatin into compacted heterochromatin domains and loosely packed euchromatin plays a significant role in governing gene expression, recent studies on a wide range of cell-types offer strong evidence to suggest that gene transcription via chromatin loop extrusion can in turn regulate the mesoscale organization of chromatin in the nucleus [2,4,14,15,[35][36][37][38][39]. Molecular dynamics simulations have been used to predict the role of active RNAPII-mediated transcription in DNA supercoiling and chromatin loop extrusion at a nano-scale [15,[40][41][42][43][44][45]. However, quantitative predictions of sizes of heterochromatin domains which organize at a nucleus-wide meso-scale level are beyond the purview of such models.…”