Structures of monomeric and dimeric PRC2:EZH1 reveal flexible modules involved in chromatin compaction

Grau, Daniel; Zhang, Yixiao; Lee, Chul-Hwan; Valencia-Sánchez, Marco; Zhang, Jenny; Wang, Miao; Holder, Marlene; Svetlov, Vladimir; Tan, Dongyan; Nudler, Evgeny; Reinberg, Danny; Walz, Thomas; Armache, Karim-Jean

doi:10.1038/s41467-020-20775-z

Structures of monomeric and dimeric PRC2:EZH1 reveal flexible modules involved in chromatin compaction

Journal Article · Thu Jan 28 23:00:00 EST 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-20775-z· OSTI ID:1816461

Grau, Daniel ^[1]; Zhang, Yixiao ^[2]; ^[3]; Valencia-Sánchez, Marco ^[1]; Zhang, Jenny ^[1]; Wang, Miao ^[1]; Holder, Marlene ^[1]; ^[3]; Tan, Dongyan ^[4]; ^[3]; Reinberg, Danny ^[3]; ^[2]; Armache, Karim-Jean ^[1]

New York Univ. (NYU), NY (United States). Grossman School of Medicine
Rockefeller Univ., New York, NY (United States)
New York Univ. (NYU), NY (United States). Grossman School of Medicine; Howard Hughes Medical Inst., Chevy Chase, MD (United States)
Stony Brook Univ., NY (United States). Medical School

Polycomb repressive complex 2 (PRC2) is a histone methyltransferase critical for maintaining gene silencing during eukaryotic development. In mammals, PRC2 activity is regulated in part by the selective incorporation of one of two paralogs of the catalytic subunit, EZH1 or EZH2. Each of these enzymes has specialized biological functions that may be partially explained by differences in the multivalent interactions they mediate with chromatin. Here, we present two cryo-EM structures of PRC2:EZH1, one as a monomer and a second one as a dimer bound to a nucleosome. When bound to nucleosome substrate, the PRC2:EZH1 dimer undergoes a dramatic conformational change. We demonstrate that mutation of a divergent EZH1/2 loop abrogates the nucleosome-binding and methyltransferase activities of PRC2:EZH1. Finally, we show that PRC2:EZH1 dimers are more effective than monomers at promoting chromatin compaction, and the divergent EZH1/2 loop is essential for this function, thereby tying together the methyltransferase, nucleosome-binding, and chromatin-compaction activities of PRC2:EZH1. We speculate that the conformational flexibility and the ability to dimerize enable PRC2 to act on the varied chromatin substrates it encounters in the cell.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); Simons Foundation; NYSTAR; National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Cancer Center Support; Laura and Isaac Perlmutter Cancer Center; David and Lucile Packard Foundation; Howard Hughes Medical Institute; National Cancer Institute; Blavatnik Family Foundation

OSTI ID:: 1816461

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 12; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Structures of monomeric and dimeric PRC2:EZH1 reveal flexible modules involved in chromatin compaction

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