Pandya-Jones, Markaki, Serizay, Chitiashvili, Mancia Leon, Damianov, et al. A protein assembly mediates Xist localization and gene silencing. Nature 2020
Abstract
Nuclear compartments have diverse roles in regulating gene expression, yet the
molecular forces and components that drive compartment formation remain largely
unclear1. The long non-coding RNA Xist establishes an intra-chromosomal compartment
by localizing at a high concentration in a territory spatially close to its transcription
locus2 and binding diverse proteins3–5 to achieve X-chromosome inactivation (XCI)6,7.
The XCI process therefore serves as a paradigm for understanding how RNA-mediated
recruitment of various proteins induces a functional compartment. The properties of
the inactive X (Xi)-compartment are known to change over time, because after initial
Xist spreading and transcriptional shutoff a state is reached in which gene silencing
remains stable even if Xist is turned off8. Here we show that the Xist RNA-binding
proteins PTBP19, MATR310, TDP-4311 and CELF112 assemble on the multivalent E-repeat
element of Xist7 and, via self-aggregation and heterotypic protein–protein interactions,
form a condensate1 in the Xi. This condensate is required for gene silencing and for the
anchoring of Xist to the Xi territory, and can be sustained in the absence of Xist.
Notably, these E-repeat-binding proteins become essential coincident with transition
to the Xist-independent XCI phase8, indicating that the condensate seeded by
the E-repeat underlies the developmental switch from Xist-dependence to
Xist-independence. Taken together, our data show that Xist forms the Xi compartment
by seeding a heteromeric condensate that consists of ubiquitous RNA-binding
proteins, revealing an unanticipated mechanism for heritable gene silencing.