KMT5C encodes robust heterochromatin retention and liquid-like behavior using limited sequence features

Cells use multiple strategies to compartmentalize functions through a combination of membrane- bound and membraneless organelles. The latter represent complex assemblies of biomolecules that coalesce into a dense phase through low affinity, multivalent interactions and undergo rapid exchange with the surrounding dilute phase. We describe a liquid-like state for the lysine methyltransferase KMT5C characterized by diffusion within heterochromatin condensates but lacking appreciable nucleoplasmic exchange. Retention was strongly correlated with reduction of condensate surface area, suggesting formation of a liquid droplet with high connectivity. This behavior mapped to a discrete domain whose activity was dependent on multiple short linear motifs. Moreover, it was strikingly resilient to marked phylogenetic differences or targeted changes in intrinsic disorder, charge, sequence, and architecture. Collectively, these findings show that a limited number of sequence features can dominantly encode multivalency, localization, and dynamic behavior within heterochromatin condensates to confer protein retention without progression to a gel or solid. ### Competing Interest Statement The authors have declared no competing interest.