The TRIP12's intrinsically disordered region induces chromatin condensates and interferes with nuclear processes.

Chromatin compaction is crucial for faithful expression and genome integrity. It implies numerous proteins and complex molecular mechanisms. The TRIP12 E3 ubiquitin ligase is tightly associated to chromatin and overexpressed in several types of cancers. We explored herein the consequences of TRIP12 overexpression on chromatin homeostasis. We demonstrated that TRIP12 overexpression leads, in a dose-dependent manner, to the formation of chromatin condensates enriched in heterochromatin marks. We delineated, within the N-terminal intrinsically disordered region of TRIP12, the region required for condensate formation that involves electrostatic interactions. We further discovered that the formation of chromatin condensates is dynamic and is in favor of a mechanism of bridging-induced phase separation. Finally, we found that the formation of TRIP12-mediated condensates alters cell cycle progression, genome accessibility, and transcription. Altogether, this study reveals a novel dynamic role for TRIP12 in chromatin compaction independently of its ubiquitin ligase activity with important consequences on nuclear processes.