Decoding the 12h-oscillator: What we've already known
Biological rhythms are "musica universalis"
Musica Universalis is an ancient philosophical concept that claims the movements of celestial bodies follow mathematical equations and resonate to produce an inaudible harmony of music, and the harmonious sounds that men make were mere an approximation of this larger harmony of the universe. Besides music, electromagnetic waves such as light and electronic signals also are presented as harmonic resonances. Despite the seemingly universal theme of harmonic resonance in various disciplines, it was not until very recently that the same harmonic resonance was discovered to also exist in biological systems. Intriguingly, contrary to the traditional belief that biological system is either at constant homeostasis (not rhythmic) or cycling with a single frequency, it is now appreciated that most biological systems have no homeostatic “set point”, but rather oscillate as composite rhythms consisting of a series of superimposed oscillations. These oscillations often cycle at different harmonics of the circadian rhythm (~24h), and among them the ~12h oscillations are found very prevalent. I posit biological rhythms are also “Musica Universalis”: while the circadian rhythm is synchronized to the 24h light/dark cycle coinciding with the Earth’s rotation, the mammalian 12h clock may have evolved from the circatidal clock, which is in turn entrained by the 12h tidal cues orchestrated mainly by the moon.
Further readings:
https://blog.drooble.com/musica-universalis-the-sound-of-the-heavens/
The eigenvalue/pencil approach
In collaboration with Dr. Antoulas, the eigenvalue/pencil method was developed to uncover all superimposed oscillations from a time series dataset. Unlike most of the current cycling transcripts-identification methodologies that require the user to define a narrow period range, the eigenvalue/pencil method does not pre-assign a period and thus permits the identification of all superimposed oscillations in an unbiased manner. For example, deconvolution of mouse hepatic Pck1 gene mRNA expression by the eigenvalue/pencil method revealed superimposed harmonic oscillations cycling at ~24h, 12h, 8h and 4h.
Further readings:
Prevalent 12h rhythms in mice and humans involved in regulating genetic information flow
When applying the eigenvalue/pencil method to all transcripts and metabolites in mouse liver, oscillations cycling at different harmonics of circadian rhythm (8h, 12h and 24h) were identified. Gene Ontology analysis of 12h-cycling mouse transcripts revealed enrichment in the entire genetic information flow process including mRNA metabolism and protein processing and unfolded protein response pathways, among many others (A). In addition to liver, 12h-cycling transcripts were also found predominantly in brown adipose tissue (BAT), skeletal muscle, white adipose tissue (WAT), aorta, lung, adrenal gland and heart, indicating a very prevalent presence of 12h-clock (B).
Besides mice, 12h rhythms of proteostasis and mRNA metabolism gene expression are also observed in primates, including hippocampus and cerebellum regions of baboons and peripheral white blood cells and dorsolateral prefrontal cortex of humans.
Further readings:
Zhu et al., Cell Metabolism, 2017
Zhu et al., Journal of Endocrine Society, 2018
Pan et al., PLoS Biology, 2020
12h oscillator is transcriptionally regulated by XBP1s, independently from the circadian clock.
Consistent with the strong enrichment of ER stress and unfolded protein response (URP) pathways in 12h-cycling hepatic transcriptome, 12h cycling of UPR transcription factor XBP1s and ATF4 was found in mouse liver. Furthermore, 12h-cycling of XBP1s expression was found in tunicamycin-synchronized MEFs and is independent from the circadian clock. Both the total level of Xbp1 mRNA (the combined level of Xbp1s and Xbp1us) and its splicing efficiency exhibited robust 12h rhythms both in mouse liver in vivo and in MEFs in vitro. Knock-down of Xbp1 further abolished cell-autonomous 12h rhythms of Eif2ak3 (a 12h-clock target gene) promoter-driven dGFP intensity in single MEF. In XBP1 liver-specific knockout mice, global ~12h, but not circadian rhythms of gene expression was either abolished or dampened.
Further readings:
Zhu et al., Cell Metabolism, 2017
12h oscillator protects against NAFLD in mice
We recently showed that liver-specific ablation of the 12h-oscillator due to XBP1 liver ablation is associated with substantially accelerated liver aging, characterized by a much earlier onset of fatty liver, mitochondria dysfunction, increased ER stress and dysregulated lipid metabolism observed in 5-8 months old XBP1 LKO mice. Since the ablation of the 12h transcriptome precedes the liver aging phenotype, we speculate that the 12h-oscillator dysregulation could drive liver aging. Since the hepatic core circadian clock remains intact both during aging and in XBP1 LKO mice, 12h-oscillator dysregulation likely can cause hepatic aging independently from the circadian clock.
Further readings:
Zhu et al., Cell Metabolism, 2017
12h-clock is evolutionarily conserved
We postulate that the mammalian 12h clock evolved from the ancient circatidal clock of marine animals, which adapt their behaviors to the 12h rhythms of ebb and flow of the tides. Conserved 12h rhythms of gene expression are found in marine animals possessing dominant circatidal clocks (such as a limpet Cellana rota), nematode, zebrafish, fly, mouse and baboon.
Further readings:
Zhu et al., Cell Metabolism, 2017
