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First published online October 22, 2008
doi: 10.1242/10.1242/jcs.035048

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Ligand modulation of REV-ERB function resets the peripheral circadian clock in a phasic manner

David Ray^2,

Andrew Loudon^1,

¹ Faculty of Life Sciences, A. V. Hill Building, Oxford Road, Manchester M13 9PT, UK
² Medical and Human Sciences, A. V. Hill Building, Oxford Road, Manchester M13 9PT, UK
³ GlaxoSmithKline, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA
⁴ GlaxoSmithKline, Discovery Biology, Respiratory CEDD, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK

Author for correspondence (e-mail: david.w.ray{at}manchester.ac.uk)

Author for correspondence (e-mail: andrew.loudon{at}manchester.ac.uk)

Accepted 1 August 2008

The nuclear receptor REV-ERB is a key negative-feedback regulator of the biological clock. REV-ERB binds to ROR elements of the Bmal1 (Arntl) promoter and represses Bmal1 transcription. This stabilizing negative loop is important for precise control of the circadian pacemaker. In the present study, we identified a novel synthetic REV-ERB ligand, which enhances the recruitment of nuclear receptor co-repressor (NCoR) to REV-ERB. In order to explore REV-ERB action on resetting responses of the molecular clock, we first established the rhythmic transcription profile and expression level of REV-ERB in Rat-1 fibroblasts. When applied at different phases of the circadian oscillation to cell models containing stably transfected Bmal1::Luc or Per2::Luc, the REV-ERB ligand induced phase-dependent bi-directional phase shifts. When the phase changes were plotted against time, a clear phase response curve was revealed, with a significant peak-to-trough amplitude of ca. 5 hours. The phase-resetting effect was also observed when the compound was applied to primary lung fibroblasts and ectopic lung slices from transgenic PER2::Luc mice. Therefore, similar regulation of REV-ERB function by endogenous ligands, such as heme, is likely to be an important mechanism for clock resetting. In addition, we identify a new means to generate phasic shifts in the clock.

Key words: Nuclear hormone receptor, Circadian clock, Resetting, Phase response curve

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