Abstract
Chromosomes have a complex architecture in the cell nucleus, which serves vital functional purposes, yet its structure and folding mechanisms remain still incompletely understood. Here we show that genome-wide chromatin architecture data, as mapped by Hi-C methods across mammalian cell types and chromosomes, are well described by classical scaling concepts of polymer physics, from the sub-Mb to chromosomal scales. Chromatin is a complex mixture of different regions, folded in the conformational classes predicted by polymer thermodynamics. The contact matrix of the Sox9 locus, a region linked to severe human congenital diseases, is derived with high accuracy in mESCs and its molecular determinants identified by the theory; Sox9 self-assembles hierarchically in higher-order domains, involving abundant many-body contacts. Our approach is also applied to the Bmp7 locus. Finally, the model predictions on the effects of mutations on folding are tested against available data on a deletion in the Xist locus. Our results can help progressing new diagnostic tools for diseases linked to chromatin misfolding.
Highlights
Chromosomes have a complex architecture in the cell nucleus, which serves vital functional purposes, yet its structure and folding mechanisms remain still incompletely understood
In the SBS model, a chromatin filament is represented at a coarse-grained level as a Self-Avoiding (SAW) string of beads interacting with diffusing binders (Fig. 1a)
Chain of beads interacting with molecular binders having a concentration, c, and a binding affinity EInt. (b) Polymer physics dictates that the model different stable architectural classes correspond to the different phases of its phase diagram: at low EInt or c, the polymer is open and randomly folded in its coil phase; above its Θ-point transition, in the globule phase it is closed in more compact conformations as signalled by a drop in its gyration radius (Figure S1a); in the closed state, at higher values of EInt or c, its binders have a transition form a disordered to an ordered arrangement, as shown by their Structure Factor (Figure S1b)
Summary
Chromosomes have a complex architecture in the cell nucleus, which serves vital functional purposes, yet its structure and folding mechanisms remain still incompletely understood. We considered the case of a block-copolymer with two types of beads (red/green) alternated in two pairs of blocks along the polymer chain, interacting each with a different type of binders (red/green, Fig. 3a, see Supplementary Materials and Methods).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
