SS18 regulates pluripotent-somatic transition through phase separation

The transition from pluripotent to somatic states marks a critical event in mammalian development, but remains largely unresolved. Here we report the identification of SS18 as a regulator for pluripotent to somatic transition or PST by CRISPR-based whole genome screens. Mechanistically, SS18 forms microscopic condensates in nuclei through a C-terminal intrinsically disordered region (IDR) rich in tyrosine, which, once mutated, no longer form condensates nor rescue SS18 −/− defect in PST. Yet, the IDR alone is not sufficient to rescue the defect even though it can form condensates indistinguishable from the wild type protein. We further show that its N-terminal 70aa is required for PST by interacting with the Brg/Brahma-associated factor (BAF) complex, and remains functional even swapped onto unrelated IDRs or even an artificial 24 tyrosine polypeptide. Finally, we show that SS18 mediates BAF assembly through phase separation to regulate PST. These studies suggest that SS18 plays a role in the pluripotent to somatic interface and undergoes liquid-liquid phase separation through a unique tyrosine-based mechanism.