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

Research output: Contribution to journalArticlepeer-review

191 Scopus citations


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 (US)
Pages (from-to)1448-1462.e14
Issue number6
StatePublished - May 30 2019
Externally publishedYes


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

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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