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Predicting chromatin architecture from models of polymer physics

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Abstract

We review the picture of chromatin large-scale 3D organization emerging from the analysis of Hi-C data and polymer modeling. In higher mammals, Hi-C contact maps reveal a complex higher-order organization, extending from the sub-Mb to chromosomal scales, hierarchically folded in a structure of domains-within-domains (metaTADs). The domain folding hierarchy is partially conserved throughout differentiation, and deeply correlated to epigenomic features. Rearrangements in the metaTAD topology relate to gene expression modifications: in particular, in neuronal differentiation models, topologically associated domains (TADs) tend to have coherent expression changes within architecturally conserved metaTAD niches. To identify the nature of architectural domains and their molecular determinants within a principled approach, we discuss models based on polymer physics. We show that basic concepts of interacting polymer physics explain chromatin spatial organization across chromosomal scales and cell types. The 3D structure of genomic loci can be derived with high accuracy and its molecular determinants identified by crossing information with epigenomic databases. In particular, we illustrate the case of the Sox9 locus, linked to human congenital disorders. The model in-silico predictions on the effects of genomic rearrangements are confirmed by available 5C data. That can help establishing new diagnostic tools for diseases linked to chromatin mis-folding, such as congenital disorders and cancer.

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Abbreviations

CTCF:

CCCTC-binding factor

FISH:

Fluorescence in situ hybridization

mESC:

mouse embryonic stem cell

NPC:

Neural precursor cell

SBS:

Strings & Binders

TAD:

Topologically associated domain

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Acknowledgements

Work supported by grants to MN from the NIH ID 1U54DK107977-01 and CINECA ISCRA ID HP10CYFPS5 and HP10CRTY8P. MN also acknowledges computer resources from INFN, CINECA, and Scope at the University of Naples.

Author Contributions

M.N. designed the study; S.B., A.M.C., C.A., M.N. developed the project; A.M.C., C.A., S.B., A.E. run the computer simulations and performed the analyses; A.M.C., C.A., S.B., M.N. wrote the manuscript.

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Authors and Affiliations

  1. Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, CNR-SPIN, Complesso Universitario di Monte Sant’Angelo, 80126, Naples, Italy

    Simona Bianco, Andrea M. Chiariello, Carlo Annunziatella, Andrea Esposito & Mario Nicodemi

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  1. Simona Bianco
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  2. Andrea M. Chiariello
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  3. Carlo Annunziatella
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  4. Andrea Esposito
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  5. Mario Nicodemi
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Corresponding author

Correspondence to Mario Nicodemi.

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The authors declare no conflict of interest.

Additional information

Responsible editor: Nick Gilbert and Davide Marenduzzo.

Simona Bianco, Andrea M. Chiariello, and Carlo Annunziatella have equal contribution.

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Bianco, S., Chiariello, A.M., Annunziatella, C. et al. Predicting chromatin architecture from models of polymer physics. Chromosome Res 25, 25–34 (2017). https://doi.org/10.1007/s10577-016-9545-5

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  • DOI: https://doi.org/10.1007/s10577-016-9545-5

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