Oral Presentation 16th Asian Conference on Transcription 2019

Context-dependent master-regulator: molecular basis for the regulation of the histone methyltransferase PRC2 (910)

Chen Davidovich 1 2
  1. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia
  2. EMBL-Australia and the ARC Centre of Excellence in Advanced Molecular Imaging, Clayton, VIC, Australia

The polycomb repressive complex 2 (PRC2) is a histone methyltransferase that maintains cell identity during development in all multicellular organisms. At the molecular level, PRC2 mark repressed genes and chromatin domains with the H3K27me3 repressive epigenetic mark. The interactions between PRC2 to some of its accessory subunits increase its enzymatic activity, while interactions with RNA inhibits it. PRC2 binds to RNA with high affinity and low sequence specificity, with preference to G-tracts and G-quadruplex-forming sequences [1]. Observations of high-affinity and inhibitory interactions between PRC2 to RNA opened a mechanistic conundrum: how can PRC2 methylate histones within the RNA-rich environment of the nucleus?
      We recently mapped the RNA-binding surfaces of PRC2 and identified an RNA-binding patch within its allosteric regulatory site, adjacent to the methyltransferase centre [2]. Accordingly, RNA-mediated inhibition of PRC2 is alleviated by allosteric activation using H3K27me3 histone-tail peptides. Most common types of holo-PRC2 complexes bind RNA, providing a unified model to explain how RNA and allosteric stimuli antagonistically regulate the enzymatic activity of PRC2. I will present results from our ongoing work, revealing how positive and negative effectors regulates PRC2 at the molecular level, within the context of transcriptional regulation.



[1] X. Wang, et al., T.R. Cech & C. Davidovich, Mol Cell. (2017); “Targeting of Polycomb Repressive Complex 2 to RNA by Short Repeats of Consecutive Guanines.”

[2] Q. Zhang, et al. R. Bonasio & C. Davidovich. Nat Struct Mol Biol. (2019); “RNA exploits an exposed regulatory site to inhibit the enzymatic activity of PRC2.”