Abstract
The circadian clock is a molecular and cellular oscillator found in most mammalian tissues that regulates rhythmic physiology and behavior. Numerous investigations have addressed the contribution of circadian rhythmicity to cellular, organ, and organismal physiology. We recently developed a method to look at transcriptional oscillations with unprecedented precision and accuracy using high-density time sampling. Here, we report a comparison of oscillating transcription from mouse liver, NIH3T3, and U2OS cells. Several surprising observations resulted from this study, including a 100-fold difference in the number of cycling transcripts in autonomous cellular models of the oscillator versus tissues harvested from intact mice. Strikingly, we found two clusters of genes that cycle at the second and third harmonic of circadian rhythmicity in liver, but not cultured cells. Validation experiments show that 12-hour oscillatory transcripts occur in several other peripheral tissues as well including heart, kidney, and lungs. These harmonics are lost ex vivo, as well as under restricted feeding conditions. Taken in sum, these studies illustrate the importance of time sampling with respect to multiple testing, suggest caution in use of autonomous cellular models to study clock output, and demonstrate the existence of harmonics of circadian gene expression in the mouse.
Highlights
Circadian rhythms are daily, 24-hour (h) oscillations in physiology and behavior such as food consumption, blood pressure, metabolism, body temperature, and locomotor activity [1,2]
We identified over 3,000 different transcripts in the mouse liver that cycle with a period length of approximately 24 hours
We identified two classes of genes which cycle with period lengths of 12 and 8 hours; i.e., harmonics of the circadian clock
Summary
24-hour (h) oscillations in physiology and behavior such as food consumption, blood pressure, metabolism, body temperature, and locomotor activity [1,2]. These rhythms are thought to give an adaptive advantage by allowing an organism to anticipate changes in the environment and regulate physiology . The central loci of the mammalian clock are two small clusters of hypothalamic neurons called the suprachiasmatic nuclei (SCN), which constitute the master pacemaker that orchestrates rhythmic patterns of behavior and physiology throughout the organism [7]. These peripheral clocks are principally regulated by stimuli downstream from the SCN, and are entrained by the SCN via a number of different physiological signals such as glucocorticoid production, core body temperature, or cAMP input (e.g. [7,10])
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