GSE120696
G-tract RNA removes Polycomb Repressive Complex 2 from genes
Polycomb Repressive Complex 2 (PRC2) maintains repression of genes specific for other cell types but associates with genes ectopically in cancer. How PRC2 is removed from genes is unknown but this knowledge may allow the targeted reversal of deleterious PRC2 recruitment events. We show that G-tract RNA specifically removes PRC2 from genes in human and mouse cells. PRC2 preferentially binds G-tracts within nascent pre-mRNAs, especially within predicted G-quadruplex structures. G-quadruplex RNA evicts the PRC2 catalytic core from the substrate nucleosome. PRC2 transfers from chromatin to RNA upon gene activation and chromatin-associated G-tract RNA removes PRC2 and depletes H3K27me3 from genes. Targeting G-tract RNA to CDKN2A in malignant rhabdoid tumor cells reactivates the gene and induces senescence. These data support a model in which pre-mRNA evicts PRC2 during gene activation and provides the means to selectively remove PRC2 from specific genes. Overall design: Input iCLIP libraries matching Suz12, Fus and hnRNPC were generated from mESC Ezh2 fl/fl without tamoxifen. IP samples are in GSE66831.