Histone mono-ubiquitination by a Clock–Bmal1 complex. Mus musculus musculus

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 in turn represses Clock–Bmal1 activity. We found that Clock–Bmal1 recruits the Ddb1–Cullin-4 ubiquitin ligase to Per, Cry, and other circadian target genes. Histone 2B mono-ubiquitination at Per genes was rhythmic and depended on Bmal1, Ddb1, and Cullin-4a. Depletion of Ddb1–Cullin-4a or independent reduction of Histone 2B mono-ubiquitination caused defective circadian feedback and markedly reduced the association of the Per complex with DNA-bound Clock–Bmal1. Clock–Bmal1 thus marks target 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 mechanism for specificity of circadian feedback.