Single-molecule and in silico dissection of the interaction between Polycomb repressive complex 2 and chromatin.

Proceedings of the National Academy of Sciences of the United States of America
R. LeicherShixin Liu

Abstract

Polycomb repressive complex 2 (PRC2) installs and spreads repressive histone methylation marks on eukaryotic chromosomes. Because of the key roles that PRC2 plays in development and disease, how this epigenetic machinery interacts with DNA and nucleosomes is of major interest. Nonetheless, the mechanism by which PRC2 engages with native-like chromatin remains incompletely understood. In this work, we employ single-molecule force spectroscopy and molecular dynamics simulations to dissect the behavior of PRC2 on polynucleosome arrays. Our results reveal an unexpectedly diverse repertoire of PRC2 binding configurations on chromatin. Besides reproducing known binding modes in which PRC2 interacts with bare DNA, mononucleosomes, and adjacent nucleosome pairs, our data also provide direct evidence that PRC2 can bridge pairs of distal nucleosomes. In particular, the "1-3" bridging mode, in which PRC2 engages two nucleosomes separated by one spacer nucleosome, is a preferred low-energy configuration. Moreover, we show that the distribution and stability of different PRC2-chromatin interaction modes are modulated by accessory subunits, oncogenic histone mutations, and the methylation state of chromatin. Overall, these findings have impl...Continue Reading

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Citations

Jun 1, 2021·Nucleic Acids Research·Xingcheng LinBin Zhang
Jul 10, 2021·The Journal of Chemical Physics·Xingcheng LinBin Zhang

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Methods Mentioned

BETA
optical tweezers
atomic force microscopy
force measurements
AFM
immunoprecipitation
ChIP-seq
chemical modification
size-exclusion chromatography
electrophoresis
ion-exchange chromatography

Software Mentioned

ForceExtensionAnalyzer
Force - Extension Analyzer
Force
- Extension Analyzer
EMAN2
learn
Scikit

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