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

TLDR

The mammalian circadian system comprises a master pacemaker in the SCN and peripheral clocks that are autonomous yet require SCN‑driven synchronization, raising the possibility that peripheral gene rhythms are governed by local oscillators, systemic signals, or both. The study aimed to distinguish whether peripheral circadian gene expression is driven by local hepatocyte clocks or systemic cues by creating a mouse with a doxycycline‑controlled, conditionally active liver clock. Researchers examined genome‑wide liver gene expression in mice with either active or arrested hepatocyte oscillators, using a conditional Bmal1 repression system to toggle the liver clock. The analysis showed that most liver genes depend on functional hepatocyte clocks for rhythmicity, but 31 genes—including mPer2—oscillated regardless of liver clock activity, implying that systemic signals can drive circadian transcription and offering a plausible mechanism for phase entrainment of peripheral clocks.

Abstract

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.