Binding of different histone marks differentially regulates the activity and specificity of polycomb repressive complex 2 (PRC2).
The polycomb repressive complex 2 (PRC2) is the major methyltransferase for H3K27 methylation, a modification critical for maintaining repressed gene expression programs throughout development. It has been previously shown that PRC2 maintains histone methylation patterns during DNA replication in part through its ability to bind to H3K27me3. However, the mechanism by which PRC2 recognizes H3K27me3 is unclear. Here we show that the WD40 domain of EED, a PRC2 component, is a methyllysine histone-binding domain. The crystal structures of apo-EED and EED in complex respectively with five different trimethyllysine histone peptides reveal that EED binds these peptides via the top face of its β-propeller architecture. The ammonium group of the trimethyllysine is accommodated by an aromatic cage formed by three aromatic residues, while its aliphatic chain is flanked by a fourth aromatic residue. Our structural data provide an explanation for the preferential recognition of the Ala-Arg-Lys-Ser motif-containing trimethylated H3K27, H3K9, and H1K26 marks by EED over lower methylation states and other histone methyllysine marks. More importantly, we found that binding of different histone marks by EED differentially regulates the activity and specificity of PRC2. Whereas the H3K27me3 mark stimulates the histone methyltransferase activity of PRC2, the H1K26me3 mark inhibits PRC2 methyltransferase activity on the nucleosome. Moreover, H1K26me3 binding switches the specificity of PRC2 from methylating H3K27 to EED. In addition to determining the molecular basis of EED-methyllysine recognition, our work provides the biochemical characterization of how the activity of a histone methyltransferase is oppositely regulated by two histone marks.
Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON, Canada.
Chao
C
Xu
Chuanbing
C
Bian
Wei
W
Yang
Marek
M
Galka
Hui
H
Ouyang
Chen
C
Chen
Wei
W
Qiu
Huadong
H
Liu
Amanda E
AE
Jones
Farrell
F
MacKenzie
Patricia
P
Pan
Shawn Shun-Cheng
SS
Li
Hengbin
H
Wang
Jinrong
J
Min
D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D011485:Protein Binding; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D056505:Retinoblastoma-Binding Protein 4 / Q000378:metabolism; D056524:Retinoblastoma-Binding Protein 7 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C491488:EED protein, human; D006657:Histones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C082637:RBBP4 protein, human; C490746:RBBP7 protein, human; D012097:Repressor Proteins; D056505:Retinoblastoma-Binding Protein 4; D056524:Retinoblastoma-Binding Protein 7; C430461:SUZ12 protein, human; D014157:Transcription Factors; D008780:Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2