title: Histone monoubiquitination by Clock-Bmal1 complex marks Per1 and Per2 genes for circadian feedback.
abstract: Circadian rhythms in mammals are driven by a feedback loop in which the transcription factor Clock-Bmal1 activates expression of Per and Cry proteins, which together form a large nuclear complex (Per complex) that represses Clock-Bmal1 activity. We found that mouse Clock-Bmal1 recruits the Ddb1-Cullin-4 ubiquitin ligase to Per (Per1 and Per2), Cry (Cry1 and Cry2) and other circadian target genes. Histone H2B monoubiquitination at Per genes was rhythmic and depended on Bmal1, Ddb1 and Cullin-4a. Depletion of Ddb1-Cullin-4a or an independent decrease in H2B monoubiquitination caused defective circadian feedback and decreased the association of the Per complex with DNA-bound Clock-Bmal1. Clock-Bmal1 thus covalently marks Per genes for subsequent recruitment of the Per complex. Our results reveal a chromatin-mediated signal from the positive to the negative limb of the clock that provides a licensing mechanism for circadian feedback.
authors: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Alfred G
authors: AG
authors: Tamayo
authors: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Hao A
authors: HA
authors: Duong
authors: Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany.
authors: Maria S
authors: MS
authors: Robles
authors: Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany.
authors: Matthias
authors: M
authors: Mann
authors: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Charles J
authors: CJ
authors: Weitz
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D002853:Chromatography, Liquid; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D044842:Cullin Proteins / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D025461:Feedback, Physiological / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D009842:Oligopeptides / Q000235:genetics; D056950:Period Circadian Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D054875:Ubiquitination
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C491940:Cul4a protein, mouse; D044842:Cullin Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C490415:Ddb1 protein, mouse; D006657:Histones; D046912:Multiprotein Complexes; D009842:Oligopeptides; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D056926:CLOCK Proteins; C538944:Clock protein, mouse