How enzymatic activity is involved in chromatin organization

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.

Fusion dynamics and size-dependent droplet microstructure in ssDNA mediated protein phase separation

“…An example is observed in the presence of type II topoisomerase enzymes, where wall-like substructures can emerge through microphase separation within euchromatic domains, which form via the phase separation of chromatin. 82 Consistent with these observations, we identified an inhomogeneous structural feature within the condensate formed by H1 and ssDNA. Moreover, we have discovered that the microstructure of the condensate is dependent on its size.…”

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

“…Quantifying biochemical reactions by using the kinetic equations is an approach often used in systems biology, while the properties arising from the connectivity of repeated units along a chain have been studied in polymer physics: our approach is the fusion of the soft matter physics and the systems biology. It is very different from other theories of heterochromatin assembly, which are based on the theory of phase separation 4 – 16 .…”

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

“…Quantifying biochemical reactions by using the kinetic equations is an approach often used in systems biology, while the properties arising from the connectivity of repeated units along a chain have been studied in polymer physics: our approach is the fusion of the soft matter physics and the systems biology. 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.…”