Central Government Versus Local Control

RESEARCH HIGHLIGHTS

CIRCADIAN GENETICS Central government versus local control

A fundamental change in our drives circadian rhythmicity — and in cultured liver explants — where understanding of mammalian is negatively controlled by another systemic signals cannot operate. In circadian biology came with the protein, REV-ERBα (also known liver explants from mice in which realization that the mechanisms as NR1D1). The authors generated BMAL1 is downregulated, circadian that drive daily rhythms are present transgenic mice in which Rev-erba Per2 expression was abolished. So, not only in a master pacemaker is expressed in the liver only, under it seems that Per2 expression can be in the brain, but also in most cells the control of tetracycline-responsive driven by local clocks in the liver as throughout the body. This means elements. So, the expression of well as by systemic cues. that circadian gene expression in BMAL1 could be turned on or off This study provides several new peripheral tissues might be under through Rev-erba expression in a insights into mammalian circadian the control of either local clocks tightly controlled way using dietary biology. First, local oscillators and or systemic circadian cues that are supplements. systemic cues both seem to regulate driven by the master pacemaker. Kornmann and colleagues used circadian patterns of gene expression A new study reveals that in fact both microarray hybridization to assess in peripheral tissues. Second, the fact forms of control are important. alterations in genome-wide expression that an oscillator component, PER2, To investigate the ‘power- patterns when BMALI expression is can be regulated independently of sharing’ between central and local repressed in the liver. For most tran- the local clock mechanisms makes it clocks, Kornmann and colleagues scripts that usually show a circadian a potential point for synchronization devised a method to inactivate expression pattern, normal cycling of local oscillators by the central the clock mechanism specifi- was altered when BMAL1 levels were pacemaker. Kornmann and col- cally in mouse liver cells. low, indicating their dependence on leagues already have evidence that The transcription the functioning of the local oscillator PER2 expression is temperature factor BMAL1 in the liver. However, a smaller subset dependent. Exploring the roles of (also known of transcripts that fall into this class body temperature and other potential as ARNTL) were unaffected by the downregula- systemic cues that regulate circadian is an essential tion of BMAL1 expression. These expression in peripheral tissues will component of are good candidates for genes whose be an important next step. the mammalian circadian regulation is controlled by Louisa Flintoft oscillator — systemic cues.

the molecular Intriguingly, one of the genes ORIGINAL RESEARCH PAPER mechanism that that fell into this latter category was Kornmann, B. et al. System-driven and period homologue 2 (Per2), another oscillator-dependent circadian transcription in mice with a conditionally active liver clock. key component of the oscillator PLoS Biol. 5, e34 (2007) mechanism — a surprising finding as FURTHER READING Bell-Pedersen, D. et al. Per2 is transcriptionally activated by Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nature Rev. Genet. BMAL1. The authors investigated the 6, 544–556 (2005) relative contributions of these two WEB SITE modes of Per2 regulation by moni- Ueli Schibler’s web site: http://www.molbio.unige.ch/schibler/index.php toring the expression of this gene

RESEARCH HIGHLIGHTS ADVISORS MICHAEL AKAM RALPH J. GREENSPAN PETER KOOPMAN JOHN QUAKENBUSH VIRGINIA WALBOT University of Cambridge, UK The Neurosciences Institute, University of Queensland, Australia Dana-Farber Cancer Institute and Stanford University, USA SEAN B. CARROLL California, USA LEONID KRUGLYAK Harvard School of Public Health, DETLEF WEIGEL Max Planck Institute University of Wisconsin, USA YOSHIHIDE HAYASHIZAKI Fred Hutchinson Cancer Research Boston, USA for Developmental Biology, Germany NANCY J. COX Riken Genomic Sciences Center, Center, USA JANET ROSSANT PHIL ZAMORE University of Chicago, USA Japan BARBARA MEYER Mount Sinai Hospital, Toronto, Canada University of Massachusetts, USA SUSAN FORSBURG University of MARK JOBLING University of California, Berkeley, MARC VIDAL Dana-Farber Cancer LEONARD I. ZON Southern California, USA University of Leicester, UK USA Institute, Boston, USA Children’s Hospital, Boston, USA