Hi-C-constrained physical models of human chromosomes recover functionally-related properties of genome organization
Marco Di Stefano, Jonas Paulsen, Tonje G. Lien, Eivind Hovig & Cristian Micheletti
Scientific Reports 6, Article number: 35985 (2016)
doi: 10.1038/srep35985
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Biological physics Computational biophysics
Received: 06 June 2016 Accepted: 30 September 2016 Published online: 27 October 2016
Abstract
Combining genome-wide structural models with phenomenological data is at the forefront of efforts to understand the organizational principles regulating the human genome. Here, we use chromosome-chromosome contact data as knowledge-based constraints for large-scale three-dimensional models of the human diploid genome. The resulting models remain minimally entangled and acquire several functional features that are observed in vivo and that were never used as input for the model. We find, for instance, that gene-rich, active regions are drawn towards the nuclear center, while gene poor and lamina associated domains are pushed to the periphery. These and other properties persist upon adding local contact constraints, suggesting their compatibility with non-local constraints for the genome organization. The results show that suitable combinations of data analysis and physical modelling can expose the unexpectedly rich functionally-related properties implicit in chromosome-chromosome contact data. Specific directions are suggested for further developments based on combining experimental data analysis and genomic structural modelling.
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How to cite this article: Di Stefano, M. et al. Hi-C-constrained physical models of human chromosomes recover functionally-related properties of genome organization. Sci. Rep. 6, 35985; doi: 10.1038/srep35985 (2016).
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Acknowledgements
We are grateful to Marc A. Marti-Renom, Davide Baù, and Angelo Rosa for useful discussions. This work was supported by The Norwegian Cancer Society [grant 71220-PR-2006-0433]; the Research Council of Norway; and the Italian Ministry of Education [grant PRIN 2010HXAW77].
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Author notes
Marco Di Stefano & Jonas Paulsen
These authors contributed equally to this work.
Affiliations
SISSA, International School for Advanced Studies, Trieste, I-34136, Italy
Marco Di Stefano & Cristian Micheletti
Institute of Basic Medical Sciences, University of Oslo, Oslo, 0317, Norway
Jonas Paulsen
University of Oslo, Department of Mathematics, Oslo, 0316, Norway
Tonje G. Lien
Institute for Cancer Research, Oslo University Hospital, Department of Tumor Biology, Oslo, 0310, Norway
Eivind Hovig
University of Oslo, Department of Informatics, Oslo, 0316, Norway
Eivind Hovig
Institute of Cancer Genetics and Informatics, Oslo, 0310, Norway
Eivind Hovig
Contributions
M.D.S., J.P., E.H. and C.M. conceived and designed the experiments; J.P. and T.G.L. performed statistical analyses; M.D.S. performed the molecular dynamics simulations; M.D.S. and J.P. analysed the data and implemented the analysis tools; M.D.S., J.P., E.H. and C.M. wrote the paper.
Competing interests
The authors declare no competing financial interests.
Corresponding author
Correspondence to Marco Di Stefano.
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