SS18 is a phase-separation protein relocating from pluripotent to somatic loci during mESC differentiation [ChIP-Seq Dataset 1]

The transition from pluripotent to somatic states marks a critical checkpoint in mammalian development. How this is regulated remains largely unresolved. Here we report the identification of SS18 by whole genome CRISPR screen as a checkpoint regulator. SS18 regulates pluripotent to somatic transition or PST by relocating from pluripotent loci to somatic ones accompanied by corresponding chromatin closing-opening and remodeling of SS18-centric protein complexes. Mechanistically, SS18 forms phase separation granules (PSG) with an intrinsically disordered region (IDR) rich in tyrosine (Y), which, once mutated, no longer form PSG nor rescue SS18-/- defect in PST. These results reveal that rapid cell fate decision can be achieved by massive redistribution of chromatin remodeling37 complexes through phase separation. We analyzed H3K27ac binding during differentiation and the dynamic changes of binding sites of Ss18 in the process of differentiation triggered by JUN in mESCs, EB and EpiSCs.