Andrea Fontana — Università di Napoli "Federico II" e INFN Napoli #
Physical principles of phase-separation action on DNA folding associated to aberrant gene activation #
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 [2] 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 these looping mechanisms on loop-extrusion. Finally, leveraging our molecular dynamics simulations, we compare our findings with experimental data [1] and show that phase-separation properties of the chimera can be harnessed to prevent enhancer-gene contacts, thereby offering a potential strategy for cancer prevention [3].

[1] J. H. Ahn et al., “Phase separation drives aberrant chromatin looping and cancer development”. Nature 595, 591-595 (2021). 

[2] A. M. Chiariello, F. Corberi, M. Salerno, “The Interplay between Phase Separation and Gene-Enhancer Communication: A Theoretical Study”. Biophys. J. 119, 873-883 (2020). 

[3] Guha, Fontana et al., “Loop-extrusion and polymer phase-separation can co-exist at the single-molecule level to shape chromatin folding”. bioRxiv (2025).