RNA exploits an exposed regulatory site to inhibit the enzymatic activity of PRC2

Qi Zhang, Nicholas J. McKenzie, Robert Warneford-Thomson, Emma H. Gail, Sarena F. Flanigan, Brady M. Owen, Richard Lauman, Vitalina Levina, Benjamin A. Garcia, Ralf B. Schittenhelm, Roberto Bonasio, Chen Davidovich

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identity during development in multicellular organisms by marking repressed genes and chromatin domains. In addition to four core subunits, PRC2 comprises multiple accessory subunits that vary in their composition during cellular differentiation and define two major holo-PRC2 complexes: PRC2.1 and PRC2.2. PRC2 binds to RNA, which inhibits its enzymatic activity, but the mechanism of RNA-mediated inhibition of holo-PRC2 is poorly understood. Here we present in vivo and in vitro protein-RNA interaction maps and identify an RNA-binding patch within the allosteric regulatory site of human and mouse PRC2, adjacent to the methyltransferase center. RNA-mediated inhibition of holo-PRC2 is relieved by allosteric activation of PRC2 by H3K27me3 and JARID2-K116me3 peptides. Both holo-PRC2.1 and holo-PRC2.2 bind RNA, providing a unified model to explain how RNA and allosteric stimuli antagonistically regulate the enzymatic activity of PRC2.

Original languageEnglish
Pages (from-to)237-247
Number of pages11
JournalNature Structural and Molecular Biology
Issue number3
StatePublished - Mar 1 2019


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