Distinct polymer physics principles govern chromatin dynamics in mouse and Drosophila topological domains

Abstract

BackgroundIn higher eukaryotes, the genome is partitioned into large "Topologically Associating Domains" (TADs) in which the chromatin displays favoured long-range contacts. While a crumpled/fractal globule organization has received experimental supports at higher-order levels, the organization principles that govern chromatin dynamics within these TADs remain unclear. Using simple polymer models, we previously showed that, in mouse liver cells, gene-rich domains tend to adopt a statistical helix shape when no significant locus-specific interaction takes place.ResultsHere, we use data from diverse 3C-derived methods to explore chromatin dynamics within mouse and Drosophila TADs. In mouse Embryonic Stem Cells (mESC), that possess large TADs (median size of 840 kb), we show that the statistical helix model, but not globule models, is relevant not only in gene-rich TADs, but also in gene-poor and gene-desert TADs. Interestingly, this statistical helix organization is considerably relaxed in mESC compared to liver cells, indicating that the impact of the constraints responsible for this organization is weaker in pluripotent cells. Finally, depletion of histone H1 in mESC alters local chromatin flexibility but not the statistical helix organization. In Drosophila, which possesses TADs of smaller sizes (median size of 70 kb), we show that, while chromatin compaction and flexibility are finely tuned according to the epigenetic landscape, chromatin dynamics within TADs is generally compatible with an unconstrained polymer configuration.ConclusionsModels issued from polymer physics can accurately describe the organization principles governing chromatin dynamics in both mouse and Drosophila TADs. However, constraints applied on this dynamics within mammalian TADs have a peculiar impact resulting in a statistical helix organization.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1786-8) contains supplementary material, which is available to authorized users.

High-salt–recovered sequences are associated with the active chromosomal compartment and with large ribonucleoprotein complexes including nuclear bodies

“…Recruitment into nuclear bodies may confine specific chromatin regions, thus limiting their diffusion into the nuclear space and favoring functional interactions required for genomic regulations during the interphase. This is particularly true for long-range inter-TAD chromatin interactions, since chromatin dynamics at this level displays extremely low contact frequencies while being essential for many genomic functions (Dixon et al 2012;Nora et al 2012;Rao et al 2014;Ea et al 2015b). For example, by use of 4C-seq, it was shown that Cajal body-associated regions are enriched in highly expressed histone genes and snRNA loci, thus forming intra-and inter-chromosomal clusters (Wang et al 2016a).…”

Role of H1 linker histones in mammalian development and stem cell differentiation

“…The proper level of chromatin flexibility and dynamicity seems to be necessary for chromatin remodeling during development and cellular differentiation, as both the increase of H1 binding affinity in ESCs (by overexpression of the H1 0 mutant with two C-terminal domains) and the failure to increase H1 binding by dephosphorylation during MEL differentiation (by overexpression of a H1 0 mutant mimicking the constitutively phosphorylated H1 0 ) inhibit cellular differentiation in respective mouse ESCs and erythroleukemia cells [141, 146, 150]. In addition, H1 depletion reduces chromatin flexibility in gene-rich topologically associating domains (TADs) [163]. …”

Genome supranucleosomal organization and genetic susceptibility to diseases

“…TADs existence and distribution, as well as the genome segregation into active and inactive compartments have been unraveled using genome-wide Hi-C. TADs organize the genome into a modular and presumably functional structure at the sub-megabase scale [37]. Chromatin loops and TADs have also been investigated experimentally using local quantitative and high-resolution chromosome conformation capture technique (3C-qPCR) [38,39]. Such experiments using 3C-qPCR clarified the distinction between the TADs as originally evidenced in [34] and [35], of size 200 kb to 1Mb (median size about 800 kb) and structures of various sizes termed chromosome contact domains [40], among which the smallest ones rather correspond to chromatin loops embedding a single gene and its proximal regulatory sequences [41].…”