Brain-specific rescue of Clock reveals system-driven transcriptional rhythms in peripheral tissue

Michael E. Hughes, Hee Kyung Hong, Jason L. Chong, Alejandra A. Indacochea, Samuel S. Lee, Michael Han, Joseph S. Takahashi, John B. Hogenesch

Research output: Contribution to journalArticle

59 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1002835
JournalPLoS Genetics
Volume8
Issue number7
DOIs
StatePublished - Jul 2012

Fingerprint

Suprachiasmatic Nucleus
brain
liver
gene
Liver
Brain
circadian rhythm
mice
Genes
Circadian Clocks
defect
genes
Darkness
Periodicity
Microarray Analysis
Circadian Rhythm
oscillation
Cues
animal
mutants

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Hughes, M. E., Hong, H. K., Chong, J. L., Indacochea, A. A., Lee, S. S., Han, M., ... Hogenesch, J. B. (2012). Brain-specific rescue of Clock reveals system-driven transcriptional rhythms in peripheral tissue. PLoS Genetics, 8(7), [e1002835]. https://doi.org/10.1371/journal.pgen.1002835

Brain-specific rescue of Clock reveals system-driven transcriptional rhythms in peripheral tissue. / Hughes, Michael E.; Hong, Hee Kyung; Chong, Jason L.; Indacochea, Alejandra A.; Lee, Samuel S.; Han, Michael; Takahashi, Joseph S.; Hogenesch, John B.

In: PLoS Genetics, Vol. 8, No. 7, e1002835, 07.2012.

Research output: Contribution to journalArticle

Hughes, ME, Hong, HK, Chong, JL, Indacochea, AA, Lee, SS, Han, M, Takahashi, JS & Hogenesch, JB 2012, 'Brain-specific rescue of Clock reveals system-driven transcriptional rhythms in peripheral tissue', PLoS Genetics, vol. 8, no. 7, e1002835. https://doi.org/10.1371/journal.pgen.1002835
Hughes, Michael E. ; Hong, Hee Kyung ; Chong, Jason L. ; Indacochea, Alejandra A. ; Lee, Samuel S. ; Han, Michael ; Takahashi, Joseph S. ; Hogenesch, John B. / Brain-specific rescue of Clock reveals system-driven transcriptional rhythms in peripheral tissue. In: PLoS Genetics. 2012 ; Vol. 8, No. 7.
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