Xist lncRNA forms silencing granules that induce heterochromatin formation and repressive complexes recruitment by phase separation

Xist long non-coding RNA induces heterochromatinization of the X-chromosome by accumulating in large ribonucleoprotein assemblies. We suggest that Xist regulates X chromosome inactivation by recruiting RNA-binding proteins via a mechanism of liquid-liquid phase separation. To support this hypothesis, we provide evidence that Xist forms ribonucleoprotein condensates that are similiar in size, shape and protein composition to paraspeackles and stress granules. We show that Xist interactome is particularly enriched in proteins that are intrinsically disordered and capable of phase separating. We suggest that Xist reinforces Xi heterochromatinization by sequestering repressive complexes, such as Polycomb proteins, in an indirect way through phase separation. This process is complementary to the canonical chromatin-mediated recruitment.