The coordination of circadian timing in brain and peripheral organs
Ueli Schibler, Benoit Kornmann, Camille Saini, Hans Reinke, Olivier Schaad & Charna Dibner
The mammalian circadian timing system influences most physiology, including sleep-wake cycles, cardiovascular activity, body temperature, renal plasma flow, intestinal peristaltic, metabolism, xenobiotic detoxification, and many endocrine functions. Circadian pacemakers were originally believed to exist only in a few specialized cell types, such as neurons of the suprachiasmatic nucleus (SCN). However, this view has been challenged by the discovery that self-sustained and cell-autonomous circadian clocks exist in most peripheral cell types. Hence, rhythmic gene expression in peripheral organs can be driven by cycling systemic cues controlled by the SCN (the master pacemaker), by local oscillators, or by both. In order to discriminate between system- and oscillator-driven genes in the liver, we generated a mouse model in which circadian oscillators in hepatocytes can be switched on and off at will. The system is based on the liver-specific overexpression of the nuclear orphan receptor REV-ERB-α from a doxycycline-dependent transgene. In the absence of doxycycline, REV-ERB-α represses transcription of the essential clock gene Bmal1 and thereby arrests hepatocyte oscillators. In the presence of doxycycline, the Rev-erb-α transgene becomes silenced, and hepatocyte oscillator function is re-established. Genome-wide profiling of the liver circadian transcriptome revealed about 350 rhythmically expressed transcripts. Less than 10% of these transcripts display cyclic accumulation with high amplitude and magnitude in the absence of doxycycline, suggesting that the cyclic transcription of most circadian genes is influenced by local oscillators. Of interest, however, mPer2, an essential clock gene, and several heat shock protein (HSP) genes show similar circadian expression in the presence and absence of functional hepatocyte clocks. At least in part, the system-driven cyclic expression of mPer2 and Hsp genes is due to the circadian activation of heat shock transcription factor 1 (HSF1). The roles of HSF1 and other transcription factors in the synchronization of peripheral oscillators will be discussed.