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

Nat Struct Mol Biol. 2021 Jan;28(1):103-117. doi: 10.1038/s41594-020-00535-9. Epub 2021 Jan 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Line
  • Embryonic Stem Cells / metabolism
  • Gene Expression Regulation / genetics*
  • Histones / metabolism
  • Methylation
  • Mice
  • Nucleotide Motifs / genetics
  • Polycomb Repressive Complex 2 / metabolism*
  • Promoter Regions, Genetic / genetics
  • Protein Biosynthesis / genetics
  • Protein Biosynthesis / physiology*
  • RNA / genetics
  • RNA / metabolism*
  • RNA Polymerase II / metabolism*
  • Transcription, Genetic / genetics
  • Transcriptional Activation / genetics

Substances

  • Histones
  • RNA
  • Polycomb Repressive Complex 2
  • RNA Polymerase II