Histone monoubiquitination by Clock-Bmal1 complex marks Per1 and Per2 genes for circadian feedback

Nature Structural & Molecular Biology
Alfred G TamayoCharles J Weitz

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.

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Citations

Jun 4, 2016·Molecular Cell·Lauren N Booth, Anne Brunet
Aug 9, 2016·Trends in Biochemical Sciences·Jennifer M HurleyJay C Dunlap
Dec 19, 2016·Nature Reviews. Genetics·Joseph S Takahashi
Feb 26, 2016·Scientific Reports·Danilo E F L FlôresShin Yamazaki
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Nov 8, 2018·The European Journal of Neuroscience·Clark Rosensweig, Carla B Green
Jul 28, 2020·Journal of Neurochemistry·Shashank Bangalore Srikanta, Nicolas Cermakian
Feb 26, 2016·Journal of Biological Rhythms·Ziv ZwighaftGad Asher
Nov 28, 2017·Journal of Biological Rhythms·Louise L HansenGerben van Ooijen
Dec 25, 2019·Scientific Reports·Jong-Chan ParkKang-Yell Choi
Jan 17, 2020·Journal of Molecular Biology·Carrie L Partch
May 1, 2021·International Journal of Molecular Sciences·Hussam IbrahimHans Reinke
Jul 30, 2019·Journal of Proteome Research·Gerald DayebgadohMichael P Washburn

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