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

M Conte and E Irani and AM Chiariello and A Abraham and S Bianco and A Esposito and M Nicodemi, NATURE COMMUNICATIONS, 13, 4070 (2022).

DOI: 10.1038/s41467-022-31856-6

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. Two main mechanisms have been proposed to shape 3D genome architecture - loop extrusion and phase separation. Here the authors combine these mechanisms in polymer models in a manner that best fits 3D genome, based on both Hi-C and super-resolution locus imaging data, proposing that these two physical processes can indeed coexist simultaneously within cells to define loops and TADs.

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