Discovery of circadian harmonics
We profiled global gene expression over two full days using Affymetrix microarrays. We identified rhythmic transcripts in the mouse liver and pituitary, as well as fibroblasts (NIH3T3) and osteosarcoma cells (U2OS). To our surprise, we found several hundred genes cycling with period lengths much shorter than 24 hours (Fig. 1). These ultradian rhythms had period lengths of ~8 and ~12 hours -- i.e., the second and third harmonics of the core circadian oscillation.
Subsequently, we have shown that these rhythms are found in tissues throughout the body. Moreover, they are found in fruit flies as well, suggesting that circadian harmonics are a common feature of animal transcriptional rhythms. At a mechanistic level, 12 hour rhythms require both a central and peripheral circadian oscillator, indicating that these rhythms are ultimately downstream of the conventional circadian clock. Typically, they are involved in cellular responses to stress, suggesting that ultradian transcriptional rhythms respond to twice daily stresses.
System-driven circadian oscillations
In collaboration with the Takahashi laboratory, we profiled transcriptional rhythms in mice with and without a defective circadian clock in the liver. Although most rhythmic genes are lost due to the ablation of the local circadian oscillator, nearly 100 genes continue to cycle with appropriate period lengths and phases (Fig. 2). Consequently, these persistent rhythms may form the molecular basis by which the central clock drives peripheral oscillations. Strikingly, many core clock genes continue to oscillate in the absence of a local clock, implying that the promoters of these genes have evolved to be directly responsive to circulating, systemic cues from the central nervous system.
Rhythms of snoRNA host genes
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Department of Biology
University of Missouri, St. Louis