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Exploring Chromosomal Structural Heterogeneity Across Multiple Cell Lines

View ORCID ProfileRyan R. Cheng, Vinicius Contessoto, View ORCID ProfileErez Lieberman Aiden, View ORCID ProfilePeter G. Wolynes, Michele Di Pierro, José N. Onuchic
doi: https://doi.org/10.1101/2020.03.21.001917
Ryan R. Cheng
1Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005
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  • For correspondence: ryan.r.cheng@gmail.com m.dipierro@northeastern.edu jonuchic@rice.edu
Vinicius Contessoto
1Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005
2Brazilian Biorenewables National Laboratory – LNBR, Brazilian Center for Research in Energy and Materials – CNPEM, Campinas, SP, Brazil
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Erez Lieberman Aiden
1Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005
3Center for Genome Architecture, Baylor College of Medicine, Houston, Texas 77030
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Peter G. Wolynes
1Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005
4Department of Chemistry, Rice University, Houston, Texas 77005
5Department of Physics & Astronomy, Rice University, Houston, Texas 77005
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Michele Di Pierro
1Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005
6Department of Physics, Northeastern University, Boston, Massachusetts 02115
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  • For correspondence: ryan.r.cheng@gmail.com m.dipierro@northeastern.edu jonuchic@rice.edu
José N. Onuchic
1Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005
5Department of Physics & Astronomy, Rice University, Houston, Texas 77005
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  • For correspondence: ryan.r.cheng@gmail.com m.dipierro@northeastern.edu jonuchic@rice.edu
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Abstract

We study the structural ensembles of human chromosomes across different cell types. Using computer simulations, we generate cell-specific 3D chromosomal structures and compare them to recently published chromatin structures obtained through microscopy. We demonstrate using a combination of machine learning and polymer physics simulations that epigenetic information can be used to predict the structural ensembles of multiple human cell lines. The chromosomal structures obtained in silico are quantitatively consistent with those obtained through microscopy as well as DNA-DNA proximity ligation assays. Theory predicts that chromosome structures are fluid and can only be described by an ensemble, which is consistent with the observation that chromosomes exhibit no unique fold. Nevertheless, our analysis of both structures from simulation and microscopy reveals that short segments of chromatin make transitions between a closed conformation and an open dumbbell conformation. This conformational transition appears to be consistent with a two-state process with an effective free energy cost of about four times the effective information theoretic temperature. Finally, we study the conformational changes associated with the switching of genomic compartments observed in human cell lines. Genetically identical but epigenetically distinct cell types appear to rearrange their respective structural ensembles to expose segments of transcriptionally active chromatin, belonging to the A genomic compartment, towards the surface of the chromosome, while inactive segments, belonging to the B compartment, move to the interior. The formation of genomic compartments resembles hydrophobic collapse in protein folding, with the aggregation of denser and predominantly inactive chromatin driving the positioning of active chromatin toward the surface of individual chromosomal territories.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Figure 2E was added to show the positioning of the genes. The experimental 3D structures examined in this manuscript (of Bintu et al, Science, 2018) were erroneously referred to as obtained via "super-resolution microscopy". The manuscript has been corrected to reflect that those structures were obtained using diffraction-limited methods. Several additional typos were fixed, including "Genonic" -> "Genomic" in Figures 1 and S1. The introduction text was reorganized. The Supporting Information was appended at the end of the manuscript file.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 21, 2020.
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Exploring Chromosomal Structural Heterogeneity Across Multiple Cell Lines
Ryan R. Cheng, Vinicius Contessoto, Erez Lieberman Aiden, Peter G. Wolynes, Michele Di Pierro, José N. Onuchic
bioRxiv 2020.03.21.001917; doi: https://doi.org/10.1101/2020.03.21.001917
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Exploring Chromosomal Structural Heterogeneity Across Multiple Cell Lines
Ryan R. Cheng, Vinicius Contessoto, Erez Lieberman Aiden, Peter G. Wolynes, Michele Di Pierro, José N. Onuchic
bioRxiv 2020.03.21.001917; doi: https://doi.org/10.1101/2020.03.21.001917

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