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Chromatin folding variability across single-cells results from state degeneracy in phase-separation

Mattia Conte, Luca Fiorillo, Simona Bianco, Andrea M. Chiariello, Andrea Esposito, Mario Nicodemi
doi: https://doi.org/10.1101/2020.05.16.099275
Mattia Conte
1Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, 80126 Naples, Italy
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Luca Fiorillo
1Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, 80126 Naples, Italy
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Simona Bianco
1Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, 80126 Naples, Italy
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Andrea M. Chiariello
1Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, 80126 Naples, Italy
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Andrea Esposito
1Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, 80126 Naples, Italy
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Mario Nicodemi
1Dipartimento di Fisica, Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo, 80126 Naples, Italy
2Berlin Institute for Medical Systems Biology, Max-Delbrück Centre (MDC) for Molecular Medicine, Berlin, Germany
3Berlin Institute of Health (BIH), MDC-Berlin, Germany
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Abstract

Chromosome spatial organization controls functional interactions between genes and regulators, yet the molecular and physical mechanisms underlying folding at the single DNA molecule level remain to be understood. Here we employ models of polymer physics to investigate the conformations of two 2Mb-wide DNA loci in human HCT116 and IMR90 wild-type and cohesin depleted cells. Model predictions on the 3D structure of single-molecules are consistently validated against super-resolution single-cell imaging data, providing evidence that the architecture of the studied loci is controlled by a thermodynamics mechanism of polymer phase separation whereby chromatin self-assembles in segregated globules. The process is driven by interactions between distinct types of cognate binding sites, correlating each with a different combination of chromatin factors, including CTCF, cohesin and histone marks. The intrinsic thermodynamics degeneracy of conformations results in a broad structural and time variability of single-molecules, reflected in their varying TAD-like contact patterns. Globules breathe in time, inducing stochastic unspecific interactions, yet they produce stable, compact environments where specific contacts become highly favored between regions enriched for cognate binding sites, albeit characterized by weak biochemical affinities. Cohesin depletion tends to reverse globule phase separation into a coil, randomly folded state, resulting in much more variable contacts across single-molecules, hence erasing population-averaged patterns. Overall, globule phase separation appears to be a robust, reversible mechanism of chromatin organization, where stochasticity and specificity coexist.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 16, 2020.
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Chromatin folding variability across single-cells results from state degeneracy in phase-separation
Mattia Conte, Luca Fiorillo, Simona Bianco, Andrea M. Chiariello, Andrea Esposito, Mario Nicodemi
bioRxiv 2020.05.16.099275; doi: https://doi.org/10.1101/2020.05.16.099275
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Chromatin folding variability across single-cells results from state degeneracy in phase-separation
Mattia Conte, Luca Fiorillo, Simona Bianco, Andrea M. Chiariello, Andrea Esposito, Mario Nicodemi
bioRxiv 2020.05.16.099275; doi: https://doi.org/10.1101/2020.05.16.099275

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