PRC2 engages a bivalent H3K27M-H3K27me3 dinucleosome inhibitor.

TitlePRC2 engages a bivalent H3K27M-H3K27me3 dinucleosome inhibitor.
Publication TypeJournal Article
Year of Publication2019
AuthorsDiehl, KL, Ge, EJ, Weinberg, DN, Jani, KS, C Allis, D, Muir, TW
JournalProc Natl Acad Sci U S A
Volume116
Issue44
Pagination22152-22157
Date Published2019 10 29
ISSN1091-6490
KeywordsAmino Acid Substitution, Binding Sites, Cell Line, Histone Methyltransferases, Histones, Humans, Models, Molecular, Polycomb Repressive Complex 2
Abstract

<p>A lysine-to-methionine mutation at lysine 27 of histone 3 (H3K27M) has been shown to promote oncogenesis in a subset of pediatric gliomas. While there is evidence that this "oncohistone" mutation acts by inhibiting the histone methyltransferase PRC2, the details of this proposed mechanism nevertheless continue to be debated. Recent evidence suggests that PRC2 must simultaneously bind both H3K27M and H3K27me3 to experience competitive inhibition of its methyltransferase activity. In this work, we used PRC2 inhibitor treatments in a transgenic H3K27M cell line to validate this dependence in a cellular context. We further used designer chromatin inhibitors to probe the geometric constraints of PRC2 engagement of H3K27M and H3K27me3 in a biochemical setting. We found that PRC2 binds to a bivalent inhibitor unit consisting of an H3K27M and an H3K27me3 nucleosome and exhibits a distance dependence in its affinity for such an inhibitor, which favors closer proximity of the 2 nucleosomes within a chromatin array. Together, our data precisely delineate fundamental aspects of the H3K27M inhibitor and support a model wherein PRC2 becomes trapped at H3K27M-H3K27me3 boundaries.</p>

DOI10.1073/pnas.1911775116
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID31611394
PubMed Central IDPMC6825254
Grant ListF30 CA224971 / CA / NCI NIH HHS / United States
P01 CA196539 / CA / NCI NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
R37 GM086868 / GM / NIGMS NIH HHS / United States
R01 GM107047 / GM / NIGMS NIH HHS / United States
P50 MH096890 / MH / NIMH NIH HHS / United States
F32 CA206418 / CA / NCI NIH HHS / United States