Polymer coil-globule phase transition is a universal folding principle of Drosophila epigenetic domains

Abstract

Localized functional domains within chromosomes, known as topologically associating domains or TADs, have been recently highlighted. In the case of Drosophila, TADs are biochemically defined by epigenetic marks, this suggesting that the 3D arrangement may be the "missing link" between epigenetic coloring and gene activity. Recent observations (Boettiger et al., Nature 2016) on Drosophila fly Kc 167 cell provide access to structural features of these domains with unprecedented resolution thanks to super resolution experiments. In particular, they give access to the distribution of the radii of gyration for domains of different linear length and associated with three different transcriptional activity states: active, inactive or repressed. Intriguingly, the observed scaling laws lacked a consistent interpretation in polymer physics. Our methodology is conceived as to extract the best information from such super-resolution data, and to place these experimental results on a theoretical framework. We show that the experimental data are compatible with the behavior of a finite-sized polymer. The same generic polymer model leads to quantitative differences between active, inactive and repressed domains. Active domains behave as pure polymer coils, while inactive and repressed domains both lie at the coil-globule cross-over. For the first time, both the "color-specificity" of the persistence length and the mean interaction energy were estimated, leading to important differences between epigenetic states.Epigenetic domains|polymer|Drosophila|coil-globule|phase transition T he 3D genome organization inside the cell nucleus is one of the most challenging questions of modern cell biology. Increasing evidence suggests that the complex and dynamical spatial arrangement of chromosomes is a keystone of gene regulation hence cell differentiation. Topologically associating domains (TADs) are one of the emerging features in this field. TADs are identified thanks to chromosome conformation capture techniques and may be defined as genomic regions whose DNA sequences physically interact with each other more frequently than with sequences outside the TAD (1). In Drosophila, these self-interacting genomic regions appear to be biochemically defined by epigenetic marks specific to various gene activity states (2). These states are called colors (3).Obtaining a physical description of the spatial organization of chromatin inside epigenetic domains is then a crucial issue. Traditional optical imaging techniques, however, cannot be used for this purpose, since their resolution is limited by diffraction to a few hundred nanometers while the typical size of epigenetic domains is in the 0.1 to 1 µm range. This limitation has been overcome by the use of super-resolution imaging, as recently achieved notably by Zhuang's and Nollmann's groups. The former used STORM to image Drosophila epigenetic domains at the single-cell level and measured the radius of gyration of each individual snapshot for every imaged domain (4). The latter used SIM to imag...

A modern challenge of polymer physics: Novel ways to study, interpret, and reconstruct chromatin structure

“…Other possible sampling strategies are based on Bayesian approaches or grid‐search algorithms . With analogous computational methods, super‐resolution microscopy data (STORM method) have been used to reconstruct chromatin 3D structure or to investigate phase‐transition and finite size properties of the chromatin chain …”

3D genome organisation in Drosophila

“…In this model, transcriptionally inactive 'null' domains, devoid of specific epigenetic marks, behave as polymers in a fractal globule [89]. There, nucleosome-nucleosome interactions are thought to be a dominant, potentially sufficient, mechanism for the high compaction of inactive domains [92]. Conversely, the relatively decondensed active domains might correspond to low nucleosome interactions [19,89,92,93].…”

“…There, nucleosome-nucleosome interactions are thought to be a dominant, potentially sufficient, mechanism for the high compaction of inactive domains [92]. Conversely, the relatively decondensed active domains might correspond to low nucleosome interactions [19,89,92,93]. Experimentally, the acetylation of histones is known to promote chromatin unfolding by decreasing nucleosome-nucleosome interactions, as the neutralisation of positive charges on histone tails on a nucleosome hinders interaction with the acidic patch of another nucleosome [94].…”

“…Experimentally, the acetylation of histones is known to promote chromatin unfolding by decreasing nucleosome-nucleosome interactions, as the neutralisation of positive charges on histone tails on a nucleosome hinders interaction with the acidic patch of another nucleosome [94]. Besides nucleosome-nucleosome interactions, computational analyses give strong interaction values for Polycomb-repressed domains, suggesting a prominent role for the molecular bridging action of Polycomb-group proteins and linker histone H1 [89,92].…”

On the relation of phase separation and Hi-C maps to epigenetics

“…The physics of polymers is well understood and predicts that very small interactions between monomers can strongly influence the whole structure because many small interactions can add up to stabilize different structures (80,81). For example, when a homo-polymer is placed in a solvent the interaction of monomers with themselves and the solvent can lead to an incompatibility that results in phase separation of the polymer (i.e., the polymer de-mixes because the energetic cost of mixing the polymer in the solvent is prohibitive), whereupon the polymer collapses into structures such as ordered globules surrounded by a solvent-rich phase (80)(81)(82)(83)(84). Notably, the formation of ordered globules is likely to be one of the consequences of folding of the nucleosome fibre "polymer" in the nucleus.…”