Structural basis for inactivation of PRC2 by G-quadruplex RNA

Science. 2023 Sep 22;381(6664):1331-1337. doi: 10.1126/science.adh0059. Epub 2023 Sep 21.


Polycomb repressive complex 2 (PRC2) silences genes through trimethylation of histone H3K27. PRC2 associates with numerous precursor messenger RNAs (pre-mRNAs) and long noncoding RNAs (lncRNAs) with a binding preference for G-quadruplex RNA. In this work, we present a 3.3-Å-resolution cryo-electron microscopy structure of PRC2 bound to a G-quadruplex RNA. Notably, RNA mediates the dimerization of PRC2 by binding both protomers and inducing a protein interface composed of two copies of the catalytic subunit EZH2, thereby blocking nucleosome DNA interaction and histone H3 tail accessibility. Furthermore, an RNA-binding loop of EZH2 facilitates the handoff between RNA and DNA, another activity implicated in PRC2 regulation by RNA. We identified a gain-of-function mutation in this loop that activates PRC2 in zebrafish. Our results reveal mechanisms for RNA-mediated regulation of a chromatin-modifying enzyme.

MeSH terms

  • Animals
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Enhancer of Zeste Homolog 2 Protein / chemistry
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • G-Quadruplexes*
  • Gain of Function Mutation
  • Histones / genetics
  • Polycomb Repressive Complex 2* / chemistry
  • Polycomb Repressive Complex 2* / genetics
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization
  • RNA Precursors*
  • RNA, Long Noncoding* / chemistry
  • RNA, Long Noncoding* / genetics
  • Zebrafish / genetics
  • Zebrafish / growth & development


  • Histones
  • Polycomb Repressive Complex 2
  • RNA Precursors
  • RNA, Long Noncoding
  • Enhancer of Zeste Homolog 2 Protein