Abstract
The circadian regulatory network is organized in a hierarchical fashion, with a central oscillator in the suprachiasmatic nuclei (SCN) orchestrating circadian oscillations in peripheral tissues. The nature of the relationship between central and peripheral oscillators, however, is poorly understood. We used the tetOFF expression system to specifically restore Clock function in the brains of ClockΔ19 mice, which have compromised circadian clocks. Rescued mice showed normal locomotor rhythms in constant darkness, with activity period lengths approximating wildtype controls. We used microarray analysis to assess whether brain-specific rescue of circadian rhythmicity was sufficient to restore circadian transcriptional output in the liver. Compared to Clock mutants, Clock-rescue mice showed significantly larger numbers of cycling transcripts with appropriate phase and period lengths, including many components of the core circadian oscillator. This indicates that the SCN oscillator overcomes local circadian defects and signals directly to the molecular clock. Interestingly, the vast majority of core clock genes in liver were responsive to Clock expression in the SCN, suggesting that core clock genes in peripheral tissues are intrinsically sensitive to SCN cues. Nevertheless, most circadian output in the liver was absent or severely low-amplitude in Clock-rescue animals, demonstrating that the majority of peripheral transcriptional rhythms depend on a fully functional local circadian oscillator. We identified several new system-driven rhythmic genes in the liver, including Alas1 and Mfsd2. Finally, we show that 12-hour transcriptional rhythms (i.e., circadian “harmonics") are disrupted by Clock loss-of-function. Brain-specific rescue of Clock converted 12-hour rhythms into 24-hour rhythms, suggesting that signaling via the central circadian oscillator is required to generate one of the two daily peaks of expression. Based on these data, we conclude that 12-hour rhythms are driven by interactions between central and peripheral circadian oscillators.
Highlights
Circadian rhythms are daily oscillations of behavior and physiology that allow organisms to anticipate and respond to predictable daily changes in their environment [1,2,3,4]
A second feedback loop is generated via RORE binding activators (Rora, Rorb, Rorc) and repressors (Rev-erb-alpha,Rev-erb-beta), whose transcription is driven by BMAL1/CLOCK [12]
We use mice with disrupted circadian rhythmicity stemming from a mutation in Clock, a key component of the circadian time-keeping mechanism
Summary
Circadian rhythms are daily oscillations of behavior and physiology that allow organisms to anticipate and respond to predictable daily changes in their environment [1,2,3,4]. In animals, these environmental variables include light, temperature, food availability, and predation. The positive arm of this feedback loop is mediated by bHLH-PAS transcription factors, BMAL1 and CLOCK/NPAS2 [10,11], which heterodimerize and drive the expression of downstream target genes Among these target genes are Period (Per) and Cryptochrome (Cry), whose protein products accumulate in the cytoplasm, associate with each other, and translocate to the nucleus. A second feedback loop is generated via RORE binding activators (Rora, Rorb, Rorc) and repressors (Rev-erb-alpha,Rev-erb-beta), whose transcription is driven by BMAL1/CLOCK [12]
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