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.
Background: The Antarctic krill Euphausia superba is a keystone species in the Southern Ocean ecosystem. This crustacean has an ancestral clock whose main components have been identified and characterized in the past few years. However, the second feedback loop, modulating clock gene expression through two transcription factors, VRI and PDP1, has yet to be described.
In mammals, molecular mechanisms of circadian rhythms involve a time-delayed negative feedback loop generating autonomous oscillations of ∼24 h. Most cell types in mammals possess circadian rhythms regulating temporal organization of cellular and physiological processes. Intriguingly, pluripotent stem cells do not possess circadian rhythms and oscillations arise after a defined period of differentiation.
MicroRNAs post-transcriptionally regulate gene expression and contribute to numerous life processes, including circadian rhythms. However, whether miRNAs contribute to zebrafish circadian regulation has not yet been investigated. Here, we showed that mature miR-219-5p, and its three pre-miRNAs, mir-219-1, mir-219-2, and mir-219-3, are rhythmically expressed primarily in Tectum opticum (TeO), Corpus cerebelli (CCe), and Crista cerellaris (CC) of the zebrafish brain.
Circadian rhythms are ∼24-h biological oscillations that enable organisms to anticipate daily environmental cycles, so that they may designate appropriate day/night functions that align with these changes. The molecular clock in animals and fungi consists of a transcription-translation feedback loop, the plant clock is comprised of multiple interlocking feedback-loops, and the cyanobacterial clock is driven by a phosphorylation cycle involving three main proteins. Despite the divergent core clock mechanisms across these systems, all circadian clocks are able to buffer period length against changes in the ambient growth environment, such as temperature and nutrients.
Aging is linked to changes in circadian rhythms and stem cell depletion, but the influence of circadian systems on skeletal aging is not fully understood.
In male mice, reduced levels of the circadian protein BMAL1 in bone marrow endothelial cells were found to disrupt the balance of extracellular matrix proteins, leading to increased breakdown of fibrillin-1 (FBN1) which affects bone health.
The loss of BMAL1 activates TGF-β signaling, promoting further breakdown of FBN1 and resulting in stem cell exhaustion and increased osteoclast activity, highlighting the role of endothelial cells in maintaining skeletal integrity during aging.
