title: The polycomb group protein EZH2 is required for mammalian circadian clock function.
abstract: We examined the importance of histone methylation by the polycomb group proteins in the mouse circadian clock mechanism. Endogenous EZH2, a polycomb group enzyme that methylates lysine 27 on histone H3, co-immunoprecipitates with CLOCK and BMAL1 throughout the circadian cycle in liver nuclear extracts. Chromatin immunoprecipitation revealed EZH2 binding and di- and trimethylation of H3K27 on both the Period 1 and Period 2 promoters. A role of EZH2 in cryptochrome-mediated transcriptional repression of the clockwork was supported by overexpression and RNA interference studies. Serum-induced circadian rhythms in NIH 3T3 cells in culture were disrupted by transfection of an RNA interfering sequence targeting EZH2. These results indicate that EZH2 is important for the maintenance of circadian rhythms and extend the activity of the polycomb group proteins to the core clockwork mechanism of mammals.
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Etchegaray
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Jason P
authors.initials: JP
authors.lastname: DeBruyne
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel CH-4058, Switzerland.
authors.forename: Antoine H F M
authors.initials: AHFM
authors.lastname: Peters
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: David R
authors.initials: DR
authors.lastname: Weaver
authors.affiliation: Research Institute of Molecular Pathology, The Vienna Biocenter, A-1030 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jenuwein
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605. Electronic address: Steven.Reppert@umassmed.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Reppert
mesh_terms: D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry; D056926:CLOCK Proteins; D002940:Circadian Rhythm; D004268:DNA-Binding Proteins / Q000502:physiology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry; D006801:Humans; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D004268:DNA-Binding Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D006657:Histones; D008239:Lysine; D063151:Polycomb Repressive Complex 2; D015534:Trans-Activators; D014157:Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C498409:EZH2 protein, human; C538943:CLOCK protein, human; C538944:Clock protein, mouse