Journal
NATURE
Volume 587, Issue 7832, Pages 145-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-020-2703-0
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Funding
- Helen Hay Whitney Foundation
- NIH [F32 GM103139, R01 GM115233, R01 GM049662, R01 MH109166]
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (BSCRC) at UCLA
- David Geffen School of Medicine at UCLA
- Jonnson Comprehensive Cancer Center at UCLA
- Howard Hughes Medical Institute
- New York Stem Cell Foundation
- Pew-Steward Scholars Program
- NIH (NICHD) [5R03HD095086, R03HD088380, R01NS104041, R01MH116220]
- Deutsche Forschungsgemeinschaft [SFB1064/A17, LE721/18-1]
- Boehringer Ingelheim Foundation
- UCLA Whitcome Fellowship
- UCLA Broad Stem Cell Research Center - Rose Hills Foundation training award
- UCLA Dissertation Year Fellowship
- Searle Scholars Program
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Nuclear compartments have diverse roles in regulating gene expression, yet the molecular forces and components that drive compartment formation remain largely unclear(1). The long non-coding RNAXistestablishes an intra-chromosomal compartment by localizing at a high concentration in a territory spatially close to its transcription locus(2)and binding diverse proteins(3-5)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 initialXistspreading and transcriptional shutoff a state is reached in which gene silencing remains stable even ifXistis turned off(8). Here we show that theXistRNA-binding proteins PTBP1(9), MATR3(10), TDP-43(11)and CELF1(12)assemble on the multivalent E-repeat element ofXist(7)and, via self-aggregation and heterotypic protein-protein interactions, form a condensate(1)in the Xi. This condensate is required for gene silencing and for the anchoring ofXistto the Xi territory, and can be sustained in the absence ofXist. Notably, these E-repeat-binding proteins become essential coincident with transition to theXist-independent XCI phase(8), indicating that the condensate seeded by the E-repeat underlies the developmental switch fromXist-dependence toXist-independence. Taken together, our data show thatXistforms the Xi compartment by seeding a heteromeric condensate that consists of ubiquitous RNA-binding proteins, revealing an unanticipated mechanism for heritable gene silencing. A protein condensate formed by multivalent interactions between the long non-coding RNA Xist and specific RNA-binding proteins drives the compartmentalization required to perpetuate gene silencing on the inactive X chromosome.
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