Nascent RNA interaction keeps PRC2 activity poised and in check

Abstract

Polycomb-repressive complex 2 (PRC2) facilitates the maintenance and inheritance of chromatin domains repressive to transcription through catalysis of methylation of histone H3 at Lys27 (H3K27me2/3). However, through its EZH2 subunit, PRC2 also binds to nascent transcripts from active genes that are devoid of H3K27me2/3 in embryonic stem cells. Here, biochemical analyses indicated that RNA interaction inhibits SET domain-containing proteins, such as PRC2, nonspecifically in vitro. However, CRISPR-mediated truncation of a PRC2-interacting nascent RNA rescued PRC2-mediated deposition of H3K27me2/3. That PRC2 activity is inhibited by interactions with nascent transcripts supports a model in which PRC2 can only mark for repression those genes silenced by transcriptional repressors.

The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2

“…In highly active genes, the elongating RNA may serve as decoy to strip PRC2 away from chromatin while the transcription machinery progresses into the gene body (Fig 2A). Importantly, this model is in excellent agreement with recent multiple independent reports, indicating that RNA inhibits the HMTase activity of PRC2 Herzog et al 2014;Kaneko et al 2014b). As one possibility, RNA may serve as an allosteric effector of HMTase activity.…”

“…The first is RNA-mediated scanning and eviction, previously referred to as the "junk mail model" (Davidovich et al 2013) or "poised and in check" (Kaneko et al 2013(Kaneko et al , 2014b. The second model suggests selected targeting to any available transcript that is not masked by other factors (Herzog et al 2014).…”

“…(F ) Scanning ("Junk Mail Model"): PRC2 interacts with nascent RNA transcripts promiscuously (Davidovich et al 2013;Kaneko et al 2013) and scans for repressive epigenetic marks or recruiting factors. Unless deposition to nucleosomes takes place, PRC2 is poised and in check (Kaneko et al 2014b) while its HMTase activity is inhibited by the RNA. (G) Maintenance: After repression is achieved, PRC2 maintains the repressed epigenetic state through direct binding to nucleosomes carrying H3K27me3 marks (Hansen et al 2008), which also stimulate its HMTase activity (Margueron et al 2009).…”

“…Previously proposed models for the recruitment of PRC2 to chromatin by lncRNA, and RNA in general, compared with RNA-independent recruitment mechanisms. (A) Eviction ("Junk Mail Model"): Promiscuous RNA binding to nascent transcripts leads to eviction of PRC2 from highly active genes (Davidovich et al 2013;Kaneko et al 2013) and inhibits its HMTase activity Herzog et al 2014;Kaneko et al 2014b). Simultaneously, H3K4me3 and H3K36me3 active chromatin marks prevent deposition of PRC2 to nucleosomes and inhibit its HMTase activity (Schmitges et al 2011;Yuan et al 2011).…”

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

“…These findings have prompted the hypothesis that interactions of PcG and TrxG proteins with specific ncRNAs can guide PcG complexes to specific sites in vivo [39,40]. Consistent with this concept, several ncRNAs support PcG and TrxG function in vivo with high specificity (for review [41]).…”