G-tract RNA removes Polycomb repressive complex 2 from genes

Abstract

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 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, 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 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

RNA-DNA strand exchange by the Drosophila Polycomb complex PRC2

“…7). If PREs (or the gene they control and in many cases are embedded in) are highly transcribed, the RNA could compete for PRC2 binding to chromatin, as has been demonstrated in vitro and in vivo 17,18,20 (Fig. 7d).…”

“…The PcG complex Polycomb Repressive Complex 2 (PRC2) has a welldescribed high affinity for RNA [13][14][15][16][17] . RNA is suggested to recruit PRC2 to specific chromatin sites 13 , but RNA binding can also compete for chromatin binding and inhibit PRC2 activity 11,[17][18][19][20] . One way for RNA to interact with the genome is by the formation of R-loops, three-stranded nucleic acid structures formed when an RNA hybridizes to a complementary DNA strand, thereby displacing the second DNA strand 21 .…”

PRC1 Catalytic Activity Is Central to Polycomb System Function

“…Through this target site selection logic, the mammalian Polycomb complexes would converge on lowly transcribed genes where they could function to protect against stochastic gene activation events that may otherwise be deleterious to the maintenance of cell-type-specific transcriptional programs (Klose et al, 2013). The responsive nature of the Polycomb system raises the question of whether some of the effects on Polycomb chromatin domain formation that we observe in the absence of PRC1 catalysis may manifest from transcription-associated eviction of Polycomb complexes (Beltran et al, 2019). For example, do the major reductions in PRC2 occupancy and H3K27me3 at Polycomb target sites directly result from loss of PRC1 catalysis and a breakdown of PRC2-dependent recognition of H2AK119ub1, or are they simply a consequence of gene activation?…”

Structure Validation of G‐Rich RNAs in Noncoding Regions of the Human Genome

“…Although the RNA G‐quadruplex topologies are limited in terms of strand orientation by the strong preference of RNA to form all‐anti all‐parallel G‐quadruplexes, dimerization or multimerization can lead to a number of different general topologies that can alter biological function immensely (Scheme ). While focusing primarily on the biological context and putting great emphasis on the role of G‐quadruplexes in regulatory systems, we wish to remark here that many cell biology studies do not involve any (or involve only sparse) biophysical characterization of G‐quadruplex structures …”