System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock

By Benoît Kornmann, O. Schaad, H. Bujard, J. Takahashi, U. Schibler. PLoS Biology, 2007

681 citations recorded by the source corpus.

The mammalian circadian timing system consists of a master pacemaker in neurons of the suprachiasmatic nucleus (SCN) and clocks of a similar molecular makeup in most peripheral body cells. Peripheral oscillators are self-sustained and cell autonomous, but they have to be synchronized by the SCN to ensure phase coherence within the organism. In principle, the rhythmic expression of genes in peripheral organs could thus be driven not only by local oscillators, but also by circadian systemic signals. To discriminate between these mechanisms, we engineered a mouse strain with a conditionally active liver clock, in which REV-ERBα represses the transcription of the essential core clock gene Bmal1 in a doxycycline-dependent manner. We examined circadian liver gene expression genome-wide in mice in which hepatocyte oscillators were either running or arrested, and found that the rhythmic transcription of most genes depended on functional hepatocyte clocks. However, we discovered 31 genes, including the core clock gene mPer2, whose expression oscillated robustly irrespective of whether the liver clock was running or not. By contrast, in liver explants cultured in vitro, circadian cycles of mPer2::luciferase bioluminescence could only be observed when hepatocyte oscillators were operational. Hence, the circadian cycles observed in the liver of intact animals without functional hepatocyte oscillators were likely generated by systemic signals. The finding that rhythmic mPer2 expression can be driven by both systemic cues and local oscillators suggests a plausible mechanism for the phase entrainment of subsidiary clocks in peripheral organs.

Subfields: Endocrine and Autonomic Systems, Physiology, Plant Science

View Paper: https://www.semanticscholar.org/paper/363f1117083a763167bfefd6b50676bdaa630af3

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Endocrine and Autonomic Systems

In Physiology

In Plant Science

Citations in the corpus

Time restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high fat diet (2012, neutral): “A number of mouse genetic models carrying wholebody-or tissue-specific perturbation of circadian oscillators (Cho et al., 2012; Kornmann et al., 2007; Lamia et al., 2008; Marcheva et al., 2010; Preitner et al., 2002; Turek et al., 2005) or key metabolic regulators (Andreelli et al., 2006; Herzig et…”
Suprachiasmatic Nucleus: Cell Autonomy and Network Properties (2010, background): “Genetic manipulations selectively disabling local oscillators have revealed that local clocks drive physiological rhythms in the retina (94) and liver (95), and that circadian regulation of gene expression in liver is driven partly by the liver clock and partly by signals emanating from the SCN (96)”
CircaDB: a database of mammalian circadian gene expression profiles (2012, background): “Several factors have catalysed a more complete description of circadian rhythms, including the advent of DNA arrays (16) and now RNA sequencing (22), powerful statistical approaches to find rhythmic genes (23) and appropriate experimental design.”
Intercellular coupling confers robustness against mutations in the SCN circadian clock network. (2007, background): “Peripheral clocks, in turn, directly regulate many local rhythms (Kornmann et al., 2007), and overt rhythms in physiology and behavior likely feed back to the SCN through hypothalamic integration (Buijs and Kalsbeek, 2001).”
The mammalian circadian timing system: organization and coordination of central and peripheral clocks. (2010, background): “We mention above that food availability during the inactivity phase will override more direct SCN-driven phase-resetting signals in the liver (194, 251).”
Timing to perfection: the biology of central and peripheral circadian clocks. (2012, background): “Discrimination between these two routes has been made possible by comparing whole transcriptome analyses of mice with or without functional liver clocks (Kornmann et al., 2007).”
Molecular Architecture of the Mammalian Circadian Clock (2013, background): “Molecular clocks located throughout the body in peripheral tissues are organized into a coherent, hierarchical system by a ‘master’ clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus [4].”