Coordination of the transcriptome and metabolome by the circadian clock

Abstract

The circadian clock governs a large array of physiological functions through the transcriptional control of a significant fraction of the genome. Disruption of the clock leads to metabolic disorders, including obesity and diabetes. As food is a potent zeitgeber (ZT) for peripheral clocks, metabolites are implicated as cellular transducers of circadian time for tissues such as the liver. From a comprehensive dataset of over 500 metabolites identified by mass spectrometry, we reveal the coordinate clock-controlled oscillation of many metabolites, including those within the amino acid and carbohydrate metabolic pathways as well as the lipid, nucleotide, and xenobiotic metabolic pathways. Using computational modeling, we present evidence of synergistic nodes between the circadian transcriptome and specific metabolic pathways. Validation of these nodes reveals that diverse metabolic pathways, including the uracil salvage pathway, oscillate in a circadian fashion and in a CLOCK-dependent manner. This integrated map illustrates the coherence within the circadian metabolome, transcriptome, and proteome and how these are connected through specific nodes that operate in concert to achieve metabolic homeostasis.C ircadian rhythms exist within a wide range of biological processes and control numerous aspects of physiology, including the sleep/wake cycle, eating, hormone and neurotransmitter secretion, and even cognitive function (1-4). Integral to the modern lifestyle is the ability to eat, sleep, work, exercise, and socialize around the clock and yet these allowances may serve as a preamble to obesity and other metabolic disorders. Recent studies reveal that a distorted circadian cycle can lead to aberrations in metabolism, producing symptoms such as obesity, insulin resistance, and others consistent with the metabolic syndrome (5-9). Whereas studies focused on night-shift and rotating shift workers emphasize the link between circadian rhythmicity and metabolism, rodent models of circadian arrhythmia also support this link (10-13). As an essential modulator of metabolism in vivo, the liver provides a cardinal domain in which to study interactions between the clock and metabolism as much of the liver transcriptome and proteome oscillates in expression or activity. These circadian characteristics of the liver are dependent largely on the zeitgeber (ZT), food (14-21).Precision within the circadian clock depends on nuclear transcriptional and translational feedback loops, but recent evidence that circadian, nontranscriptional, and nontranslational cytosolic rhythms crosstalk with nuclear rhythms to maintain circadian timing provides support for the idea that metabolites may affect the transcriptional-translational canonical clock system and vice versa (22,23). Some biochemical oscillations have been shown to cycle in a circadian fashion, such as calcium, 3′-5′-cyclic adenosine monophosphate (cAMP) and nicotinamide (NAD + ) (24-27). These oscillations feed into the clock system and can modulate circadian dynamics in vivo. Sever...

Human blood metabolite timetable indicates internal body time

“…The comparison of our identified circadian-oscillating metabolites to recent studies (13,14) is explained in SI Results and Discussion.…”

“…In mammals, for example, several clock genes regulate circadian gene expression in central and peripheral clock tissues (3)(4)(5)(6)(7)(8)(9), as well as metabolites in the blood (10)(11)(12)(13)(14)(15). Reflecting circadian regulation of such processes, the potency and toxicity of administered drugs depends on an individual's body time (BT) (16)(17)(18)(19)(20)(21)(22).…”

Immunometabolism: Is it under the eye of the clock?

“…3A and B-blue shading). Metabolomics indicate that approximately 20% of metabolites fluctuate with a circadian variation [69][70][71]. Blood glucose levels undergo time-of-day variation in humans and rodent models [72].…”

Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins

“…The core clock molecular circuitry relies on interlocked transcription-translation feedback loops that generate daily oscillations of gene expression in cultured cells and living animals (7). Many transcriptomes (8)(9)(10)(11)(12)) and more recently, several proteomics (13)(14)(15) and metabolomics studies (16)(17)(18)(19)(20)(21) highlighted the pervasive circadian control of metabolism.…”