Dipartimento di Fisica and Sezione INFN, Università degli Studi di Padova, I-35131 Padova, Italy.
SUPA, School of Physics and Astronomy, University of Edinburgh, Edinburgh EH9 3FD, United Kingdom; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom; and Centre for Mathematical Biology, and Department of Mathematical Sciences, University of Bath, North Rd, Bath BA2 7AY, United Kingdom.
Phys Rev E. 2019 Nov;100(5-1):052410. doi: 10.1103/PhysRevE.100.052410.
Epigenetics is a driving force of important and ubiquitous phenomena in nature such as cell differentiation or even metamorphosis. Opposite to its widespread role, understanding the biophysical principles that allow epigenetics to control and rewire gene regulatory networks remains an open challenge. In this work we study the effects of epigenetic modifications on the spatial folding of chromosomes-and hence on the expression of the underlying genes-by mapping the problem to a class of models known as magnetic polymers. In this work we show that a first order phase transition underlies the simultaneous spreading of certain epigenetic marks and the conformational collapse of a chromosome. Further, we describe Brownian dynamics simulations of the model in which the topology of the polymer and thermal fluctuations are fully taken into account and that confirm our mean field predictions. Extending our models to allow for nonequilibrium terms yields new stable phases which qualitatively agrees with observations in vivo. Our results show that statistical mechanics techniques applied to models of magnetic polymers can be successfully exploited to rationalize the outcomes of experiments designed to probe the interplay between a dynamic epigenetic landscape and chromatin organization.
表观遗传学是自然界中一些重要且普遍存在的现象的驱动力,例如细胞分化甚至变态。与它的广泛作用相反,理解允许表观遗传学控制和重新布线基因调控网络的生物物理原理仍然是一个开放的挑战。在这项工作中,我们通过将问题映射到一类称为磁性聚合物的模型来研究表观遗传修饰对染色体空间折叠的影响,进而对其下基因的表达产生影响。在这项工作中,我们表明,一级相变是某些表观遗传标记的同时扩散和染色体构象崩溃的基础。此外,我们描述了模型的布朗动力学模拟,其中充分考虑了聚合物的拓扑结构和热涨落,并证实了我们的平均场预测。将我们的模型扩展到允许非平衡项,产生了新的稳定相,这与体内观察结果定性一致。我们的结果表明,应用于磁性聚合物模型的统计力学技术可以成功地用于合理化旨在探测动态表观遗传景观和染色质组织之间相互作用的实验结果。