ABRAHAM, ALEX (2023) Co-existence of loop-extrusion and phase-separation at the single-molecule level to shape chromatin folding. [Tesi di dottorato]

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Abstract

In recent years, the chromosome spatial organization has emerged as a crucial factor in gene regulation. In mammalian cells, loop-extrusion and phase-separation have been proposed as the major physical mechanisms that shape this organization. Yet it is unclear how they function relative to each other in determining the chromatin architecture and whether they compete or co-exist at a single-molecule level. In this thesis, we compare various polymer physics-based models incorporating loop-extrusion and phase-separation, against multiplexed FISH data in human IMR90 and HCT116 cells. We find that the models explain average multiplexed microscopy data and bulk Hi-C data. The phase-separation-based models are found to better capture experimentally observed globule segregation of the studied loci and their cell-to-cell variability. While the loop-extrusion-based models are found to be better at reproducing higher-order contacts. Overall, the hybrid model of loop-extrusion and polymer phase-separation provides a general finer description of the data, showing that the two mechanisms can function in tandem to shape the chromatin architecture in single cells.

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