Session 4 : Molecular mechanisms of resistance

Biomolecular condensates in nuclear organization

The formation of biomolecular condensates has emerged as a mechanism that regulates various cellular processes that are dysregulated in cancer. The faithful formation and maintenance of heterochromatin is one of them. Based on observations in different model systems including fission yeast, fly, mouse and human, it has been suggested to be driven by liquid phase separation of heterochromatin protein 1 (HP1) or not. To resolve this controversy, we compared HP1 homologs from different species side-by-side in the test tube and in mammalian cells. We found that HP1 from fission yeast and fly are more disordered and have a much higher propensity to form condensates than mammalian HP1. Condensate formation of ectopic fly HP1 in mouse cells induced the spatial reorganization of heterochromatin, showing that phase separation can indeed control nuclear architecture. Gene expression was only mildly altered in cells with reorganized heterochromatin. These results suggest that the biophysical properties and the cellular function of HP1 differ across species, pointing to an evolutionary switch in heterochromatin homeostasis.