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Polymer physics indicates chromatin folding variability across single-cells results from state degeneracy in phase separation

Author

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  • Mattia Conte

    (Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo)

  • Luca Fiorillo

    (Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo)

  • Simona Bianco

    (Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo)

  • Andrea M. Chiariello

    (Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo)

  • Andrea Esposito

    (Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo)

  • Mario Nicodemi

    (Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo
    Max-Delbrück Centre (MDC) for Molecular Medicine
    Berlin Institute of Health (BIH), MDC-Berlin)

Abstract

The spatial organization of chromosomes has key functional roles, yet how chromosomes fold remains poorly understood at the single-molecule level. Here, we employ models of polymer physics to investigate DNA loci in human HCT116 and IMR90 wild-type and cohesin depleted cells. Model predictions on single-molecule structures are validated against single-cell imaging data, providing evidence that chromosomal architecture is controlled by a thermodynamics mechanism of polymer phase separation whereby chromatin self-assembles in segregated globules by combinatorial interactions of chromatin factors that include CTCF and cohesin. The thermodynamics degeneracy of single-molecule conformations results in broad structural and temporal variability of TAD-like contact patterns. Globules establish stable environments where specific contacts are highly favored over stochastic encounters. Cohesin depletion reverses phase separation into randomly folded states, erasing average interaction patterns. Overall, globule phase separation appears to be a robust yet reversible mechanism of chromatin organization where stochasticity and specificity coexist.

Suggested Citation

  • Mattia Conte & Luca Fiorillo & Simona Bianco & Andrea M. Chiariello & Andrea Esposito & Mario Nicodemi, 2020. "Polymer physics indicates chromatin folding variability across single-cells results from state degeneracy in phase separation," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17141-4
    DOI: 10.1038/s41467-020-17141-4
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    Cited by:

    1. Samuel Abassah-Oppong & Matteo Zoia & Brandon J. Mannion & Raquel Rouco & Virginie Tissières & Cailyn H. Spurrell & Virginia Roland & Fabrice Darbellay & Anja Itum & Julie Gamart & Tabitha A. Festa-Da, 2024. "A gene desert required for regulatory control of pleiotropic Shox2 expression and embryonic survival," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    2. Sangram Kadam & Kiran Kumari & Vinoth Manivannan & Shuvadip Dutta & Mithun K. Mitra & Ranjith Padinhateeri, 2023. "Predicting scale-dependent chromatin polymer properties from systematic coarse-graining," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Markus Götz & Olivier Messina & Sergio Espinola & Jean-Bernard Fiche & Marcelo Nollmann, 2022. "Multiple parameters shape the 3D chromatin structure of single nuclei at the doc locus in Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Andrea M. Chiariello & Alex Abraham & Simona Bianco & Andrea Esposito & Andrea Fontana & Francesca Vercellone & Mattia Conte & Mario Nicodemi, 2024. "Multiscale modelling of chromatin 4D organization in SARS-CoV-2 infected cells," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Mattia Conte & Ehsan Irani & Andrea M. Chiariello & Alex Abraham & Simona Bianco & Andrea Esposito & Mario Nicodemi, 2022. "Loop-extrusion and polymer phase-separation can co-exist at the single-molecule level to shape chromatin folding," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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