Histone H3 tail binds a unique sensing pocket in EZH2 to activate the PRC2 methyltransferase.

TitleHistone H3 tail binds a unique sensing pocket in EZH2 to activate the PRC2 methyltransferase.
Publication TypeJournal Article
Year of Publication2019
AuthorsJani, KS, Jain, SU, Ge, EJ, Diehl, KL, Lundgren, SM, Müller, MM, Lewis, PW, Muir, TW
JournalProc Natl Acad Sci U S A
Volume116
Issue17
Pagination8295-8300
Date Published2019 Apr 23
ISSN1091-6490
Abstract

Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2), the enzyme that catalyzes monomethylation, dimethylation, and trimethylation of lysine 27 on histone H3 (H3K27). Trimethylation at H3K27 (H3K27me3) is associated with transcriptional silencing of developmentally important genes. Intriguingly, H3K27me3 is mutually exclusive with H3K36 trimethylation on the same histone tail. Disruptions in this cross-talk result in aberrant H3K27/H3K36 methylation patterns and altered transcriptional profiles that have been implicated in tumorigenesis and other disease states. Despite their importance, the molecular details of how PRC2 "senses" H3K36 methylation are unclear. We demonstrate that PRC2 is activated in cis by the unmodified side chain of H3K36, and that this activation results in a fivefold increase in the k cat of its enzymatic activity catalyzing H3K27 methylation compared with activity on a substrate methylated at H3K36. Using a photo-cross-linking MS strategy and histone methyltransferase activity assays on PRC2 mutants, we find that EZH2 contains a specific sensing pocket for the H3K36 methylation state that allows the complex to distinguish between modified and unmodified H3K36 residues, altering enzymatic activity accordingly to preferentially methylate the unmodified nucleosome substrate. We also present evidence that this process may be disrupted in some cases of Weaver syndrome.

DOI10.1073/pnas.1819029116
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID30967505
PubMed Central IDPMC6486736
Grant ListP01 CA196539 / CA / NCI NIH HHS / United States
R01 GM086868 / GM / NIGMS NIH HHS / United States
R37 GM086868 / GM / NIGMS NIH HHS / United States