The physics of epigenetics

Abstract

In higher organisms, all cells share the same genome, but every cell expresses only a limited and specific set of genes that defines the cell type. During cell division, not only the genome, but also the cell type is inherited by the daughter cells. This intriguing phenomenon is achieved by a variety of processes that have been collectively termed epigenetics: the stable and inheritable changes in gene expression patterns. This article reviews the extremely rich and exquisitely multi-scale physical mechanisms that govern the biological processes behind the initiation, spreading and inheritance of epigenetic states. These include not only the changes in the molecular properties associated with the chemical modifications of DNA and histone proteins, such as methylation and acetylation, but also less conventional changes, typically in the the physics that governs the three-dimensional organization of the genome in cell nuclei. Strikingly, to achieve stability and heritability of epigenetic states, cells take advantage of many different physical principles, such as the universal behavior of polymers and copolymers, the general features of dynamical systems, and the electrostatic and mechanical properties related to chemical modifications of DNA and histones. By putting the complex biological literature under this new light, the emerging picture is that a limited set of general physical rules play a key role in initiating, shaping and transmitting this crucial "epigenetic landscape". This new perspective not only allows to rationalize the normal cellular functions, but also helps to understand the emergence of pathological states, in which the epigenetic landscape becomes dysfunctional.

A Polymer Model with Epigenetic Recolouring Reveals a Pathway for thede novoEstablishment and 3D organisation of Chromatin Domains

“…Although one of the current paradigms of chromosome biology and biophysics is that the epigenetic landscape directs 3D genome folding [16][17][18][19]22], an outstanding question is how the epigenetic landscape is established in the first place -and how this can be reset de novo after each cell division. In this respect, our results suggest that the inherent non-equilibrium (i.e., ATP-driven) nature of the epigenetic read-write mechanism, can provide a pathway to enlarge the possible breadth of epigenetic patterns which can be established stochastically, with respect to thermodynamic models.…”

“…Although one of the current paradigms of the field is that the epigenetic landscape and 3D genome folding are intimately related [16][17][18][19][20][21][22][23][24], most of the existing biophysical studies incorporating epigenetic dynamics have focused on 1-dimensional (1D) or mean field models [25][26][27][28][29][30][31][32][33][34]. While these models can successfully explain some aspects of the establishment, spreading, and stability of epigenetic marks, they cannot fully capture the underlying 3-dimensional (3D) dynamic organisation of the chromatin.…”

Chromosomes : étonnants polymères !

“…Et pourtant, l'organisation des chromosomes dans l'espace du noyau cellulaire recèle probablement une part des secrets du fonctionnement des organismes pluricellulaires. Chez ces organismes, en effet, toutes les cellules possèdent le même Maria Barbi (1) , Annick Lesne (1,2) , Julien Mozziconacci (1) et Jean Marc Victor (1) 1. Organisation hiérarchique de la chromatine (schéma).…”

“…Du point de vue physique, les modifica tions épigénétiques changent les consti tuants du chromosome, aussi bien à l'échelle des nucléotides qu'à celle des nucléosomes, par formation de complexes avec des protéines nucléaires [1]. On a donc affaire à un polymère particulièrement atypique : les monomères y sont euxmêmes des assemblages moléculaires complexes, dont la structure et les interactions peuvent être modifiées épigénétiquement.…”

“…Ainsi, il a été possible de simuler le comportement d'une fibre de chromatine soumise à des contraintes mécaniques, et notamment de calculer les efforts mécaniques (forces, couples) induits par une manipulation en torsion et en traction par des pinces magnétiques. L'ADN (encart, bas) est modélisé à l'aide de l'outil de simulation macromoléculaire CGMDODE (1) comme une chaîne de cylindres articulés (encart, haut) : la taille des cylindres (ici 10 bases, 3,4 nm) est inférieure aux longueurs de persistance de l'ADN, et des couples de force sont appliqués au niveau des articulations pour reproduire les propriétés élastiques de l'ADN. Sous les points de mesure, des instantanés de la simulation montrent comment la rotation appliquée à la bille (en rouge) induit la formation de structures surenroulées, appelées plectonèmes, qui « absorbent » la rotation en réduisant la longueur <z> de la molécule proportionnellement à la rotation appliquée.…”