Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3.
Human Enhancer of Zeste homolog (Ezh2) is a histone lysine methyltransferase (HKMT) associated with transcriptional repression. Ezh2 is present in several distinct complexes, one of which, PRC2, we characterized previously. Here we report an additional Ezh2 complex, PRC3. We show that the Ezh2 complexes exhibit differential targeting of specific histones for lysine methylation dependent upon the context of the histone substrates. This differential targeting is a function of the associated Eed protein within each complex. We found that Eed protein is present in four isoforms, which represent alternate translation start site usage from the same mRNA. These Eed isoforms selectively associate with distinct Ezh2-containing complexes with resultant differential targeting of their associated HKMT activity toward histone H3-K27 or histone H1-K26. Our data provide evidence for a novel mechanism regulating the substrate specificity of a chromatin-modifying enzyme through disparate translational products of a regulatory subunit.
Kuzmichev
Andrei
A
Robert Wood Johnson Medical School, Howard Hughes Medical Institute and Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.
Jenuwein
Thomas
T
Tempst
Paul
P
Reinberg
Danny
D
D000911:Antibodies, Monoclonal / Q000378:metabolism; D001665:Binding Sites; D015153:Blotting, Western; D004268:DNA-Binding Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D000071221:Enhancer of Zeste Homolog 2 Protein; D015971:Gene Expression Regulation, Enzymologic; D018390:Gene Targeting; D017930:Genes, Reporter; D005822:Genetic Vectors; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D008954:Models, Biological; D009707:Nucleosomes / Q000737:chemistry / Q000378:metabolism*; D017354:Point Mutation; D063151:Polycomb Repressive Complex 2; D011233:Precipitin Tests; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D014157:Transcription Factors
D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; C491488:EED protein, human; D006657:Histones; D009707:Nucleosomes; D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D008780:Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2