The polycomb group protein EZH2 is required for mammalian circadian clock function.
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.
Etchegaray
Jean-Pierre
JP
Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Yang
Xiaoming
X
Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
DeBruyne
Jason P
JP
Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Peters
Antoine H F M
AHFM
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel CH-4058, Switzerland.
Weaver
David R
DR
Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Jenuwein
Thomas
T
Research Institute of Molecular Pathology, The Vienna Biocenter, A-1030 Vienna, Austria.
Reppert
Steven M
SM
Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605. Electronic address: Steven.Reppert@umassmed.edu.
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*
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