Polymer model with Epigenetic Recoloring Reveals a Pathway for the de novo Establishment and 3D Organization of Chromatin Domains
D. Michieletto, E. Orlandini, and D. Marenduzzo
Phys. Rev. X 6, 041047 – Published 9 December 2016
One of the most important problems in development is how epigenetic domains can first be established, and then maintained, within cells. To address this question, we propose a framework that couples three-dimensional chromatin folding dynamics to a “recoloring” process modeling the writing of epigenetic marks. Because many intrachromatin interactions are mediated by bridging proteins, we consider a “two-state” model with self-attractive interactions between two epigenetic marks that are alike (either active or inactive). This model displays a first-order-like transition between a swollen, epigenetically disordered phase and a compact, epigenetically coherent chromatin globule. If the self-attraction strength exceeds a threshold, the chromatin dynamics becomes glassy, and the corresponding interaction network freezes. By modifying the epigenetic read-write process according to more biologically inspired assumptions, our polymer model with recoloring recapitulates the ultrasensitive response of epigenetic switches to perturbations and accounts for long-lived multidomain conformations, strikingly similar to the topologically associating domains observed in eukaryotic chromosomes.
Received 15 June 2016
Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.
Published by the American Physical Society
AUTHORS & AFFILIATIONS
D. Michieletto1, E. Orlandini2, and D. Marenduzzo1
1SUPA, School of Physics and Astronomy, University of Edinburgh, Peter Guthrie Tait Road, Edinburgh EH9 3FD, United Kingdom
2Dipartimento di Fisica e Astronomia and Sezione INFN, Università di Padova, Via Marzolo 8, Padova 35131, Italy
Epigenetic modifications are biochemical marks that form patterns along chromosomes and regulate gene expression. The epigenetic patterning of chromosomes enables cellular differentiation, while leaving the underlying DNA sequence unchanged. How these patterns are established and then maintained across cell division is far from understood, however. Here, we show that a polymer model with “recolorable” segments can explain epigenetic memory and the self-organization of long-lived epigenetic domains.
We theoretically consider a model of epigenetic switches that consists of a chromatin fiber modeled as a semiflexible chain made of beads (roughly 30 nm) connected by a harmonic potential. In our model, we assume that two similar epigenetic marks experience self-attractive interactions. We investigate how the folding dynamics of the chromatin in three dimensions is coupled to the creation of epigenetic modifications and how the model transitions between an epigenetically disordered phase and an epigenetically ordered phase. We are able to explain the physically observed phenomenon of “epigenetic memory,” in which genes that are switched off are only infrequently reactivated. In addition, we show that by breaking detailed balance, our model is able to display epigenetic domains with long-lived boundaries that last throughout the simulation runtime of a few hours and that are reminiscent of so-called “topologically associated domains,” recently observed in vivo. In conclusion, we argue that epigenetic modifications are likely modulated by a positive feedback mechanism and that their ATP-mediated regulation is key to control topologically associated domains and, ultimately, gene expression.
We expect that our findings will motivate future studies of how epigenetic domains and, consequently, gene expression are coupled with chromatin folding dynamics.