Motif-driven interactions between RNA and PRC2 are rheostats that regulate transcription elongation

Although polycomb repressive complex 2 (PRC2) is now recognized as an RNA-binding complex, the full range of binding motifs and why PRC2-RNA complexes often associate with active genes have not been elucidated. Here, we identify high-affinity RNA motifs whose mutations weaken PRC2 binding and attenuate its repressive function in mouse embryonic stem cells. Interactions occur at promoter-proximal regions and frequently coincide with pausing of RNA polymerase II (POL-II). Surprisingly, while PRC2-associated nascent transcripts are highly expressed, ablating PRC2 further upregulates expression via loss of pausing and enhanced transcription elongation. Thus, PRC2-nascent RNA complexes operate as rheostats to fine-tune transcription by regulating transitions between pausing and elongation, explaining why PRC2-RNA complexes frequently occur within active genes. Nascent RNA also targets PRC2 in cis and downregulates neighboring genes. We propose a unifying model in which RNA specifically recruits PRC2 to repress genes through POL-II pausing and, more classically, trimethylation of histone H3 at Lys27. Denaturing CLIP analyses and functional assays in mouse ESCs reveal that PRC2 interacts with nascent transcripts via specific RNA motifs to promote POL-II pausing and to control transcription elongation within non-canonical PRC2 gene targets.

Automated summary

The study reveals that PRC2 interacts with RNA to modulate gene transcription in active genes by regulating the pausing and elongation of RNA polymerase II.