Speaker
Description
Phase separation of chimeric proteins resulting from genetic mutations has been shown to trigger aberrant chromatin looping, contributing to disease development, including cancer [1]. However, the physical mechanisms regulating these processes remain unclear. In this study, we employ polymer physics models of chromatin to investigate the relationship between protein self-aggregation and chromatin structure [2]. We show that a simple model, including only protein-protein and protein-chromatin interactions, effectively explains the aberrant looping around certain oncogenes in cells expressing the NUP98-HOXA9 chimera [1], commonly found in leukemia. Moreover, when incorporating the presence of cohesin in a more complex model [3], similar results are observed, suggesting a weak dependence of this looping mechanisms from loop-extrusion. Finally, leveraging on our numerical simulations, we compare our findings with experimental data [1] and show that the phase-separation property of chimera can be harnessed to prevent enhancer-gene contacts, thereby offering a potential strategy for cancer prevention.
[1] J. H. Ahn et al., “Phase separation drives aberrant chromatin looping and cancer development”. Nature 595, 591-595 (2021).
[2] A. M. Chiariello et al., “Polymer physics of chromosome large-scale 3D organisation”. Sci. Rep. 6, 29775 (2016).
[3] M. Conte et al., “Loop-extrusion and polymer phase-separation can co-exist at the single-molecule level to shape chromatin folding”. Nat. Comm. 13, 4070 (2022).
| Role | Master/PhD student |
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