Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3.

ELife
K. FinogenovaJürg Müller

Abstract

Repression of genes by Polycomb requires that PRC2 modifies their chromatin by trimethylating lysine 27 on histone H3 (H3K27me3). At transcriptionally active genes, di- and tri-methylated H3K36 inhibit PRC2. Here, the cryo-EM structure of PRC2 on dinucleosomes reveals how binding of its catalytic subunit EZH2 to nucleosomal DNA orients the H3 N-terminus via an extended network of interactions to place H3K27 into the active site. Unmodified H3K36 occupies a critical position in the EZH2-DNA interface. Mutation of H3K36 to arginine or alanine inhibits H3K27 methylation by PRC2 on nucleosomes in vitro. Accordingly, Drosophila H3K36A and H3K36R mutants show reduced levels of H3K27me3 and defective Polycomb repression of HOX genes. The relay of interactions between EZH2, the nucleosomal DNA and the H3 N-terminus therefore creates the geometry that permits allosteric inhibition of PRC2 by methylated H3K36 in transcriptionally active chromatin.

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Nov 25, 2020·Current Opinion in Structural Biology·Eleanor GlancyAdrian P Bracken
Dec 5, 2020·Current Opinion in Cell Biology·Rodrigo Villaseñor, Tuncay Baubec
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Nov 9, 2021·Biochemical Society Transactions·Akhil Gargey IragavarapuVignesh Kasinath

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Methods Mentioned

BETA
cross-linking studies
size-exclusion chromatography
electromobility shift
ChIP-seq
confocal microscopy
genotyping
PCR
electrophoresis
ChIP

Software Mentioned

Relion
phenix
PyMOL2
STAR
Coot
STAN
tidyverse
3DFSC
MotionCor2
Fiji

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