Defining the Independence of the Liver Circadian Clock

Kevin B. Koronowski, Kenichiro Kinouchi, Patrick Simon Welz, Jacob G. Smith, Valentina M. Zinna, Jiejun Shi, Muntaha Samad, Siwei Chen, Christophe N. Magnan, Jason M. Kinchen, Wei Li, Pierre Baldi, Salvador Aznar Benitah, Paolo Sassone-Corsi

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24 Citations (Scopus)

Abstract

Mammals rely on a network of circadian clocks to control daily systemic metabolism and physiology. The central pacemaker in the suprachiasmatic nucleus (SCN) is considered hierarchically dominant over peripheral clocks, whose degree of independence, or tissue-level autonomy, has never been ascertained in vivo. Using arrhythmic Bmal1-null mice, we generated animals with reconstituted circadian expression of BMAL1 exclusively in the liver (Liver-RE). High-throughput transcriptomics and metabolomics show that the liver has independent circadian functions specific for metabolic processes such as the NAD+ salvage pathway and glycogen turnover. However, although BMAL1 occupies chromatin at most genomic targets in Liver-RE mice, circadian expression is restricted to ∼10% of normally rhythmic transcripts. Finally, rhythmic clock gene expression is lost in Liver-RE mice under constant darkness. Hence, full circadian function in the liver depends on signals emanating from other clocks, and light contributes to tissue-autonomous clock function. A autonomous branch of the liver circadian clock is independent from all other clocks yet still dependent on the light-dark cycle.

Original languageEnglish
Pages (from-to)1448-1462.e14
JournalCell
Volume177
Issue number6
DOIs
Publication statusPublished - 2019 May 30

Keywords

  • autonomous
  • bmal1
  • chromatin
  • circadian
  • clock
  • diurnal physiology
  • epigenetics
  • light
  • metabolism
  • systemic signaling

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Koronowski, K. B., Kinouchi, K., Welz, P. S., Smith, J. G., Zinna, V. M., Shi, J., Samad, M., Chen, S., Magnan, C. N., Kinchen, J. M., Li, W., Baldi, P., Benitah, S. A., & Sassone-Corsi, P. (2019). Defining the Independence of the Liver Circadian Clock. Cell, 177(6), 1448-1462.e14. https://doi.org/10.1016/j.cell.2019.04.025