Cargando…

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

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 e...

Descripción completa

Detalles Bibliográficos
Autores principales: Kornmann, Benoît, Schaad, Olivier, Bujard, Hermann, Takahashi, Joseph S, Schibler, Ueli
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1783671/
https://www.ncbi.nlm.nih.gov/pubmed/17298173
http://dx.doi.org/10.1371/journal.pbio.0050034
_version_ 1782132018362974208
author Kornmann, Benoît
Schaad, Olivier
Bujard, Hermann
Takahashi, Joseph S
Schibler, Ueli
author_facet Kornmann, Benoît
Schaad, Olivier
Bujard, Hermann
Takahashi, Joseph S
Schibler, Ueli
author_sort Kornmann, Benoît
collection PubMed
description 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.
format Text
id pubmed-1783671
institution National Center for Biotechnology Information
language English
publishDate 2007
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-17836712007-01-30 System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock Kornmann, Benoît Schaad, Olivier Bujard, Hermann Takahashi, Joseph S Schibler, Ueli PLoS Biol Research Article 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. Public Library of Science 2007-02 2007-01-30 /pmc/articles/PMC1783671/ /pubmed/17298173 http://dx.doi.org/10.1371/journal.pbio.0050034 Text en © 2007 Kornmann et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Kornmann, Benoît
Schaad, Olivier
Bujard, Hermann
Takahashi, Joseph S
Schibler, Ueli
System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock
title System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock
title_full System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock
title_fullStr System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock
title_full_unstemmed System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock
title_short System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock
title_sort system-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1783671/
https://www.ncbi.nlm.nih.gov/pubmed/17298173
http://dx.doi.org/10.1371/journal.pbio.0050034
work_keys_str_mv AT kornmannbenoit systemdrivenandoscillatordependentcircadiantranscriptioninmicewithaconditionallyactiveliverclock
AT schaadolivier systemdrivenandoscillatordependentcircadiantranscriptioninmicewithaconditionallyactiveliverclock
AT bujardhermann systemdrivenandoscillatordependentcircadiantranscriptioninmicewithaconditionallyactiveliverclock
AT takahashijosephs systemdrivenandoscillatordependentcircadiantranscriptioninmicewithaconditionallyactiveliverclock
AT schiblerueli systemdrivenandoscillatordependentcircadiantranscriptioninmicewithaconditionallyactiveliverclock