Regulation of histone methylation by automethylation of PRC2
- Xueyin Wang1,2,3,5,
- Yicheng Long1,2,5,
- Richard D. Paucek1,2,4,
- Anne R. Gooding1,2,
- Thomas Lee2,
- Rachel M. Burdorf1,2 and
- Thomas R. Cech1,2
- 1Howard Hughes Medical Institute, University of Colorado at Boulder, Boulder, Colorado 80309, USA;
- 2Department of Chemistry and Biochemistry, BioFrontiers Institute, University of Colorado at Boulder, Boulder, Colorado, 80309 USA
- Corresponding author: thomas.cech{at}colorado.edu
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↵5 These authors contributed equally to this work.
Abstract
Polycomb-repressive complex 2 (PRC2) is a histone methyltransferase that is critical for regulating transcriptional repression in mammals. Its catalytic subunit, EZH2, is responsible for the trimethylation of H3K27 and also undergoes automethylation. Using mass spectrometry analysis of recombinant human PRC2, we identified three methylated lysine residues (K510, K514, and K515) on a disordered but highly conserved loop of EZH2. Methylation of these lysines increases PRC2 histone methyltransferase activity, whereas their mutation decreases activity in vitro. De novo histone methylation in an EZH2 knockout cell line is greatly impeded by mutation of the automethylation lysines. EZH2 automethylation occurs intramolecularly (in cis) by methylation of a pseudosubstrate sequence on a flexible loop. This posttranslational modification and cis regulation of PRC2 are analogous to the activation of many protein kinases by autophosphorylation. We propose that EZH2 automethylation allows PRC2 to modulate its histone methyltransferase activity by sensing histone H3 tails, SAM concentration, and perhaps other effectors.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.328849.119.
- Received May 15, 2019.
- Accepted July 30, 2019.
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