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Review
. 2018 Jun 6;2(7):727-752.
doi: 10.1210/js.2018-00113. eCollection 2018 Jul 1.

Unveiling "Musica Universalis" of the Cell: A Brief History of Biological 12-Hour Rhythms

Bokai Zhu  1 , Clifford C Dacso  1   2   3 , Bert W O'Malley  1   3
Affiliations
Review

Unveiling "Musica Universalis" of the Cell: A Brief History of Biological 12-Hour Rhythms

Bokai Zhu et al. J Endocr Soc. .

Abstract

"Musica universalis" is an ancient philosophical concept claiming the movements of celestial bodies follow mathematical equations and resonate to produce an inaudible harmony of music, and the harmonious sounds that humans make were an approximation of this larger harmony of the universe. Besides music, electromagnetic waves such as light and electric signals also are presented as harmonic resonances. Despite the seemingly universal theme of harmonic resonance in various disciplines, it was not until recently that the same harmonic resonance was discovered also to exist in biological systems. Contrary to traditional belief that a biological system is either at stead-state or cycles 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 superimposed oscillations. These oscillations often cycle at different harmonics of the circadian rhythm, and among these, the ~12-hour oscillation is most prevalent. In this review, we focus on these 12-hour oscillations, with special attention to their evolutionary origin, regulation, and functions in mammals, as well as their relationship to the circadian rhythm. We further discuss the potential roles of the 12-hour clock in regulating hepatic steatosis, aging, and the possibility of 12-hour clock-based chronotherapy. Finally, we posit that biological rhythms are also musica universalis: whereas the circadian rhythm is synchronized to the 24-hour light/dark cycle coinciding with the Earth's rotation, the mammalian 12-hour clock may have evolved from the circatidal clock, which is entrained by the 12-hour tidal cues orchestrated by the moon.

Keywords: 12h-clock; ER stress; NAFLD; Xbp1; aging; chronotherapy; mitochondria.

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Figures

Figure 1.
Figure 1.
The concept of harmonics in physics and their biological counterpart. (A) Diagram showing the individual harmonics (200 Hz, 400 Hz, 600 Hz, 800 Hz, and 1000 Hz) as well as the composite waveform resulting from adding up all of the harmonics. (B) Distribution of periods of all oscillations identified from the hepatic gene expression microarray dataset [8] via the eigenvalue/pencil approach. The vast majority of oscillations cycle at the first (24-hour), second (12-hour), or third (8-hour) harmonic of the circadian rhythm (24 hours). (C) Representative deconvolution of Gck gene mRNA expression by the eigenvalue/pencil method. Gck expressions detected by two different probe sets are analyzed by the eigenvalue/pencil method. (i) Raw microarray data (solid line) and model fit (dashed line) for Gck hepatic expression as reported in Ref. [8]. Superimposed harmonic oscillations revealed by the eigenvalue/pencil method for probe 1 (ii) and probe 2 (iii) are shown. (iv) Amplitudes, phases, and periods of different oscillations for the two probes with the color matching the different oscillations depicted in (ii) and (iii). (D) Distribution of periods of all oscillations identified from the hepatic metabolites dataset [11] via the eigenvalue/pencil approach. The vast majority of oscillations cycle at the first (24-hour), second (12-hour), third (8-hour), or fourth (6-hour) harmonic of the circadian rhythm (24 hours).
Figure 2.
Figure 2.
Coupled 12-hour rhythms of hepatic gene expression and metabolism. (A) Heat map of mouse 12-hour cycling hepatic metabolites identified by the eigenvalue/pencil method from published metabolomic dataset [11] after hierarchical clustering. Metabolites with dominant 12-hour oscillations are highlighted in red. (B) (Top) Gene-metabolite joint pathway analysis using MetaboAnalyst [41, 42] reveals top enriched biological pathways. Both enrichment as well as topology scores are shown for each pathway. (Bottom) Representative data showing paired gene expression and metabolite oscillations. (C) Distribution of acrophases of all dominant hepatic 12-hour cycling mRNA and ribonuclesides/ribonucleotides.
Figure 3.
Figure 3.
Twelve-hour rhythms of gene expression and metabolism are cell-autonomous, established by a dedicated 12-hour clock and evolutionarily conserved. (A) Representative reads per kilobase of transcript per million mapped reads (RPKM) of normalized hepatic circadian (top) as well as 12-hour cycling (bottom) gene expression from wild-type (WT) and conventional BMAL1 knockout (KO) mice under 12-hour/12-hour light/dark conditions as reported in Ref. [86]. Data are graphed as the mean ± SEM (n = 4) and double plotted for better visualization. (B) Heat map representation of oscillations of Eif2ak3 and Per2 mRNA level after dexamethasone, tunicamycin, or glucose depletion shock treatment in MEFs. The heat map is derived from quantitative PCR data reported in Ref. [3]. A summary of the conclusion is shown in the table below. (C) Representative recordings of single-cell time lapse microscopy analysis of Eif2ak3 promoter-driven dGFP oscillation in scrambled siRNA, Bmal1 siRNA, or Xbp1 siRNA transfected MEFs. (D) Heat map of 12-hour cycling metabolites in dexamethasone-synchronized human U2OS cells under both scrambled siRNA and Bmal1 siRNA transfection conditions compiled from Ref. [11]. Twelve-hour cycling metabolites are identified by the eigenvalue/pencil method [3].
Figure 4.
Figure 4.
Twelve-hour rhythms of gene expression are evolutionarily conserved. (A) Heat map of temporal mtDNA-encoded gene expression in temperature-entrained as well as free-running C. elegans compiled from Ref. [75]. (B) Heat map of core ER homeostasis and metabolism related 12-hour cycling gene expression in both temperature-entrained as well as free-running C. elegans (left; compiled from Ref. [75]) and mouse liver under constant darkness (right; compiled from Ref. [8]). Xbp1 is highlighted in red. (C) Phylogenetic tree and relative mRNA expression of Eif2ak3, Gfpt1, and Dnajb4 in C. rota (second row; reported in Ref. [23]), Caenorhabditis elegans (third row; reported in Ref. [75]), Danio rerio (fourth row; reported in Ref. [99]), Mus musculus (fifth row; and reported in Ref. [8]), and Papio anubis (last row; reported in Ref. [100]) during a 48-hour interval. The status of the three genes was not reported for E. pulchra in the study [18]. The data for Papio anubis is double plotted for better visualization. (D) The mRNA level of Xbp1 ortholog in C. rota captured from different times of day from their natural intertidal habitat in the wild as compiled from Ref. [23]. (E) Heat map of all 280 evolutionarily 12-hour cycling gene expression in temperature-entrained as well as free-running C. elegans (left; compiled from Ref. [75]), naturally caught C. rota in tune to 12-hour cycling tidal cues under 12-hour/12-hour natural light condition (middle; compiled from Ref. [23]), and mouse liver under constant darkness (right; compiled from Ref. [8]). (F) Gene ontology analysis of enriched KEGG pathways from these 280 genes. (G) Predicted interactive network construction of these 280 proteins using STRING [102] with XBP1 highlighted by the arrow.
Figure 5.
Figure 5.
Mammalian 12-hour clock in diseases and chronotherapy. (A) Diagram summarizing the origin, regulation, function, and species conservation of 12-hour clock. Please see the main text for detailed description of each section. (B) High-fat diet disrupts the hepatic 12-hour cycling, but not circadian gene expression in mice. Heat map (left) and representative log2 normalized expression (right) of key 12-hour cycling and circadian genes under normal chow and high-fat diet conditions are compiled from Ref. [40]. The data are double plotted for better visualization. (C) Disrupted hepatic 12-hour rhythms are associated with aging. Heat map (top) and representative mRNA expression (bottom) of key 12-hour cycling and circadian gene in young and old male mice are compiled from Ref. [152]. (D) Aging-regulating genes are enriched for 12-hour rhythmicity in C. elegans. (Top) Heat map of aging-related 12-hour cycling gene expression in both temperature-entrained as well as free-running C. elegans as compiled from Ref. [75]. Of 62 genes that increase worm lifespan by 10% when knocked down postdevelopmentally [163], 38 (62%) of them showed 12-hour rhythm in temperature-entrained and free-running worms as shown in the heat map. Additionally, positive regulators of aging, including atfs-1, xbp-1, daf-16, aak-2, tcer-1, and sir-2.1, all exhibited 12-hour rhythms of gene expression. (Bottom) Heat map of mammalian ortholog of sir-2.1 (Sirt1), daf-16 (Foxo1), and aak-2 (Prkaa1 and Prkaa2) expression in mouse liver under constant darkness condition as compiled from Ref. [8]. Atfs1 and Xbp1 are highlighted in red. (E and F) Twelve-hour clock–based chronotherapy blueprint. Heat map of temporal mRNA (E) and protein (F) expression of hepatic 12-hour cycling genes with Food and Drug Administration–approved drug interactions as compiled from Refs. [8, 38]. The names of drug are indicated on the right. FEN1, FASN, and PPAT also exhibit 12-hour rhythms of mRNA expression and are highlighted in red.
Figure 6.
Figure 6.
Framework of 12-hour clock study. (A) Diagram summarizing the potential causal roles of mammalian 12-hour clock in disease development with future directions outlined below. Twelve-hour rhythms can be disrupted either by the dampening of the amplitude or alteration of the period. (B) Diagram summarizing the basis for biological system being part of “musica universalis”. ERSE, ER response element; RORE, retinoic acid–related orphan receptor response element.
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