Abstract
Chromatin of mammalian nucleus folds into discrete contact enriched regions such as Topologically Associating Domains (TADs). Folding hierarchy and internal organization of TADs is highly dynamic throughout cellular differentiation, and are correlated with gene activation and silencing. To account for multiple interacting TADs, we developed a parsimonious randomly cross-linked (RCL) polymer model that maps high frequency Hi-C encounters within and between TADs into direct loci interactions using cross-links at a given base-pair resolution. We reconstruct three TADs of the mammalian X chromosome for three stages of differentiation. We compute the radius of gyration of TADs and the encounter probability between genomic segments. We found 1) a synchronous compaction and decompaction of TADs throughout differentiation and 2) high order organization into meta-TADs resulting from weak inter-TAD interactions. Finally, the present framework allows to infer transient properties of the chromatin from steady-state statistics embedded in the Hi-C/5C data.
Highlights
Chromatin of mammalian nucleus folds into discrete contact enriched regions such as Topologically Associating Domains (TADs)
We present and apply here methodology based on polymer model that accounts for interactions between topologically associating domains (TADs) to study chromatin dynamic at long scales, an area that remains largely unexplored
We introduce our methodology to construct an randomly cross-linked (RCL) polymer from the empirical encounter probability (EP) extracted from 5C or Hi-C data, we determine their geometrical organization and characterize their distribution in space by computing the volume of TADs using the mean radius of gyration (MRG)
Summary
Chromatin of mammalian nucleus folds into discrete contact enriched regions such as Topologically Associating Domains (TADs). To account for multiple interacting TADs, we developed a parsimonious randomly cross-linked (RCL) polymer model that maps high frequency Hi-C encounters within and between TADs into direct loci interactions using cross-links at a given base-pair resolution. Mammalian chromosomes fold into discrete megabasepairs (Mbp) contact enriched regions termed topologically associating domains (TADs). We present and apply here methodology based on polymer model that accounts for interactions between TADs to study chromatin dynamic at long scales, an area that remains largely unexplored. Conformation capture contact maps provide a statistical summary of steady-state looping frequencies, but do not contain neither direct information about the size of the folded genomic section nor any transient genomic encounter times[11]. The random positions of the cross-links capture the heterogeneity of chromatin structure sampled in a large ensemble of cells
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