Modeling epigenome folding: formation and dynamics of topologically associated chromatin domains.
Bottom Line: Remarkably, recent studies indicate that these 1D epigenomic domains tend to fold into 3D topologically associated domains forming specialized nuclear chromatin compartments.We show how experiments are fully consistent with multistable conformations where topologically associated domains of the same epigenomic state interact dynamically with each other.Our approach provides a general framework to improve our understanding of chromatin folding during cell cycle and differentiation and its relation to epigenetics.
Affiliation: Laboratoire de Physique, Ecole Normale Supérieure de Lyon, CNRS UMR 5672, Lyon 69007, France.Show MeSH
Related in: MedlinePlus
Mentions: Interestingly, within epigenomic domains, regulatory sequences such as enhancers may be located far from the target genes and multiple elements that are distributed over large regions may collaborate or compete for the regulation of individual genes or gene clusters. This implies the existence of long-range mechanisms where regulatory elements could act over large genomic distances up to hundreds of kilobases or more. A possible mechanism regulating such long-range effects is the linear spreading of a regulatory signal (e.g. repressive chromatin state) from nucleation sites (e.g. silencers) to target-sites (e.g. promoters). Another non-exclusive mechanism calls into play the polymeric nature of chromatin that may induce spatial colocalization of regulatory sequences with their target. Recently, chromosome conformation capture (3C)-based studies have indeed shown that regulatory elements can act over large genomic distances by chromatin looping (8,9) forming active or repressive higher-order chromatin structure at particular developmentally regulated genes. These pairwise 3D interactions are mediated by DNA binding proteins such as insulators or cohesin and mediator (10) that would cluster in space and bridge distant regulatory sites. At a genomic scale, the contact maps of Drosophila (11,12), mouse (13) and human (13,14) chromosomes have further revealed a remarkable 3D compartmentalization where epigenomic domains fold into independent ‘spatial domains’, the so-called topologically associated domains (TADs), characterized by (i) high intra-domain contact frequencies; (ii) 3D insulation between adjacent domains; (iii) and in many cases, significant contacts between distal domains of the same chromatin type (Figures 3A and 4A). This compartmentalization is consistent with the nuclear structure, as revealed by imaging techniques such as electron microscopy and immuno-FISH (15–17), that clearly shows a phase separation between euchromatin versus heterochromatin and to some extent between the different heterochromatin types (18).
Affiliation: Laboratoire de Physique, Ecole Normale Supérieure de Lyon, CNRS UMR 5672, Lyon 69007, France.