Loop-extrusion and polymer phase-separation can co-exist at the single-molecule level to shape chromatin folding

Mattia Conte, Ehsan Irani, Andrea M. Chiariello, Alex Abraham, Simona Bianco, Andrea Esposito and Mario Nicodemi ()
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Mattia Conte: Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo
Ehsan Irani: Berlin Institute for Medical Systems Biology, Max-Delbrück Centre (MDC) for Molecular Medicine
Andrea M. Chiariello: Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo
Alex Abraham: Università di Napoli Federico II, and INFN Napoli, Complesso Universitario di Monte Sant’Angelo
Simona Bianco: Berlin Institute for Medical Systems Biology, Max-Delbrück Centre (MDC) for Molecular Medicine
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

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Loop-extrusion and phase-separation have been proposed as mechanisms that shape chromosome spatial organization. It is unclear, however, how they perform relative to each other in explaining chromatin architecture data and whether they compete or co-exist at the single-molecule level. Here, we compare models of polymer physics based on loop-extrusion and phase-separation, as well as models where both mechanisms act simultaneously in a single molecule, against multiplexed FISH data available in human loci in IMR90 and HCT116 cells. We find that the different models recapitulate bulk Hi-C and average multiplexed microscopy data. Single-molecule chromatin conformations are also well captured, especially by phase-separation based models that better reflect the experimentally reported segregation in globules of the considered genomic loci and their cell-to-cell structural variability. Such a variability is consistent with two main concurrent causes: single-cell epigenetic heterogeneity and an intrinsic thermodynamic conformational degeneracy of folding. Overall, the model combining loop-extrusion and polymer phase-separation provides a very good description of the data, particularly higher-order contacts, showing that the two mechanisms can co-exist in shaping chromatin architecture in single cells.

Date: 2022
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DOI: 10.1038/s41467-022-31856-6

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