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Cell. 2019 May 30;177(6):1448-1462.e14. doi: 10.1016/j.cell.2019.04.025.

Defining the Independence of the Liver Circadian Clock.

Author information

1
Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
2
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
3
Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
4
Institute for Genomics and Bioinformatics, Department of Computer Science, UCI, Irvine, CA 92697, USA.
5
Metabolon, Morrisville, NC 27560, USA.
6
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain. Electronic address: salvador.aznar-benitah@irbbarcelona.org.
7
Center for Epigenetics and Metabolism, U1233 INSERM, Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: psc@uci.edu.

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.

KEYWORDS:

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

PMID:
31150621
DOI:
10.1016/j.cell.2019.04.025

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