Chromosome Research

, Volume 25, Issue 1, pp 5–14 | Cite as

Modelling genome-wide topological associating domains in mouse embryonic stem cells

Original Article

Abstract

Chromosome conformation capture (3C)-based techniques such as chromosome conformation capture carbon copy (5C) and Hi-C revealed that the folding of mammalian chromosomes is highly hierarchical. A fundamental structural unit in the hierarchy is represented by topologically associating domains (TADs), sub-megabase regions of the genome within which the chromatin fibre preferentially interacts. 3C-based methods provide the mean contact probabilities between chromosomal loci, averaged over a large number of cells, and do not give immediate access to the single-cell conformations of the chromatin fibre. However, coarse-grained polymer models based on 5C data can be used to extract the single-cell conformations of single TADs. Here, we extend this approach to analyse around 2500 TADs in murine embryonic stem cells based on high-resolution Hi-C data. This allowed to predict the cell-to-cell variability in single contacts within genome-wide TADs and correlations between them. Based on these results, we predict that TADs are more similar to ideal chains than to globules in terms of their physical size and three-dimensional shape distribution. Furthermore, we show that their physical size and the degree of structural anisotropy of single TADs are correlated with the level of transcriptional activity of the genes that it harbours. Finally, we show that a large number of multiplets of genomic loci co-localize more often than expected by random, and these loci are particularly enriched in promoters, enhancers and CTCF-bound sites. These results provide the first genome-wide structural reconstruction of TADs using polymeric models obeying the laws of thermodynamics and reveal important universal trends in the correlation between chromosome structure and transcription.

Keyword

Chromatin model Hi-C data Promoter-enhancer interaction CTCF Big data 

Abbreviations

3C

Chromosome conformation capture

4C

Chromosome conformation capture-on-chip

5C

Chromosome conformation capture carbon copy

TAD

Topologically associating domain

FISH

Fluorescence in situ hybridization

ESC

Embryonic stem cell

RPKM

Reads per kilobase per million mapped reads

Supplementary material

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10577_2016_9544_MOESM3_ESM.pdf (2 mb)
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Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  1. 1.Friedrich Miescher Institute for Biomedical ResearchBaselSwitzerland
  2. 2.Center for Complexity and Biosystems and Department of PhysicsUniversità degli Studi di Milano and INFNMilanItaly

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