G-tract RNA removes Polycomb repressive complex 2 from genes.
Manuel BeltranManuel TavaresNeil JustinGarima KhandelwalJohn AmbroseBenjamin M FosterKaylee B WorlockAndrey TvardovskiySimone KunzelmannJavier HerreroTill BartkeSteven J GamblinJon R WilsonRichard G JennerPublished in: Nature structural & molecular biology (2019)
Polycomb repressive complex 2 (PRC2) maintains repression of cell-type-specific genes but also associates with genes ectopically in cancer. While it is currently unknown how PRC2 is removed from genes, such knowledge would be useful for the targeted reversal of deleterious PRC2 recruitment events. Here, we show that G-tract RNA specifically removes PRC2 from genes in human and mouse cells. PRC2 preferentially binds G tracts within nascent precursor mRNA (pre-mRNA), especially within predicted G-quadruplex structures. G-quadruplex RNA evicts the PRC2 catalytic core from the substrate nucleosome. In cells, PRC2 transfers from chromatin to pre-mRNA upon gene activation, and chromatin-associated G-tract RNA removes PRC2, leading to H3K27me3 depletion from genes. Targeting G-tract RNA to the tumor suppressor gene 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.
Keyphrases
- genome wide
- genome wide identification
- transcription factor
- genome wide analysis
- dna methylation
- copy number
- bioinformatics analysis
- induced apoptosis
- dna damage
- gene expression
- binding protein
- machine learning
- papillary thyroid
- signaling pathway
- cancer therapy
- oxidative stress
- cell cycle arrest
- mass spectrometry
- electronic health record
- young adults
- lymph node metastasis
- artificial intelligence
- squamous cell
- amino acid