The folding landscape of the epigenome

Abstract

The role of the spatial organization of chromatin in gene regulation is a long-standing but still open question. Experimentally it has been shown that the genome is segmented into epigenomic chromatin domains that are organized into hierarchical sub-nuclear spatial compartments. However, whether this non-random spatial organization only reflects or indeed contributes-and how-to the regulation of genome function remains to be elucidated. To address this question, we recently proposed a quantitative description of the folding properties of the fly genome as a function of its epigenomic landscape using a polymer model with epigenomic-driven attractions. We propose in this article, to characterize more deeply the physical properties of the 3D epigenome folding. Using an efficient lattice version of the original block copolymer model, we study the structural and dynamical properties of chromatin and show that the size of epigenomic domains and asymmetries in sizes and in interaction strengths play a critical role in the chromatin organization. Finally, we discuss the biological implications of our findings. In particular, our predictions are quantitatively compatible with experimental data and suggest a different mean of self-interaction in euchromatin versus heterochromatin domains.

Perspectives: using polymer modeling to understand the formation and function of nuclear compartments

“…The precise shapes of the phase diagram, as well as the behavior of individual blocks, are strongly dependent on the underlying pattern of chromatin states (size of blocks, number of different states, etc.) (Jost et al 2014; Olarte-Plata et al 2016). For example, larger blocks will start collapsing at weaker interaction strength due to stronger collective effects (Olarte-Plata et al 2016).…”

“…There are different ways of investigating such model: standard molecular dynamics (Rosa and Everaers 2008) or kinetic Monte-Carlo simulations (Olarte-Plata et al 2016), Gaussian self-consistent (GSC) approximation (Ramalho et al 2013; Jost et al 2014), etc. The qualitative behavior of the system is independent of the chosen method.…”

“…By varying the strength of non-specific and specific interactions, the systems exhibit a variety of different phases (Fig. 4A) (Jost et al 2014; Olarte-Plata et al 2016). For weak interactions, configurations are characteristic of an unstructured, coil phase.…”

“…(Jost et al 2014; Olarte-Plata et al 2016). For example, larger blocks will start collapsing at weaker interaction strength due to stronger collective effects (Olarte-Plata et al 2016).

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“…In particular, heteropolymer models that explicitly consider the coupling between chromatin structure and function have recently started to emerge (Barbieri et al 2012; Brackley et al 2016; Jerabek and Heermann 2012; Benedetti et al 2014; Doyle et al 2014; Ganai et al 2014; Jost et al 2014; Tark-Dame et al 2014; Nazarov et al 2015; Sanborn et al 2015; Ulianov et al 2016; Fudenberg et al 2016; Tiana et al 2016). In this perspective article, we are going to focus on some recent ideas (Jost et al 2014; Olarte-Plata et al 2016) concerning the connection between epigenome, polymer physics, and the formation of sub-Mbp domains (TADs) inside chromosome territories. Then, we will discuss the possibility that the genome compartmentalization might not be only the consequence of the genome function (the epigenome) but might actually serve as a “nanoreactor” enhancing robustness of local biochemical reaction involved in gene regulation and in particular in chromatin assembly and maintenance.…”