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Adjustment of the mouse liver transcriptome to the photoperiod

English title Adjustment of the mouse liver transcriptome to the photoperiod
Applicant Ripperger Jürgen A.
Number 135587
Funding scheme Project funding (Div. I-III)
Research institution Division de Biochimie Département de Biologie Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Molecular Biology
Start/End 01.04.2011 - 31.03.2014
Approved amount 318'924.00
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All Disciplines (3)

Discipline
Molecular Biology
Biochemistry
Genetics

Keywords (4)

Zirkadiane Uhr; Tageslängenveränderung; Chronotherapie; Lebermetabolismus

Lay Summary (German)

Lead
Viele Vorgänge im menschlichen Körper werden durch eine zirkadiane Uhr beeinflusst. Diese Uhr basiert auf dem rhythmischen Zusammenspiel zwischen aktivierenden und reprimierenden Faktoren innerhalb der Körperzellen. Die Aufgabe der zirkadianen Uhr ist es, eine Synchronisation unseres Metabolismus und unserer Physiologie mit der Umwelt zu ermöglichen. Allerdings ändert sich die äussere Tageslänge ständig über den Verlauf eines Jahres, was bedeutet, dass die zirkadiane Uhr eine gewisse Flexibilität aufweisen muss. In diesem Projekt haben wir versucht, die Auswirkungen der Veränderung der Tageslänge auf die Leber zu beschreiben.
Lay summary

Durchführung und Resultate des Forschungsprojektes

In diesem Forschungsprojekt haben wir versucht, neue Erkenntnisse über die Anpassung der Leber an eine sich verändernde Tageslänge zu gewinnen. Als Modellsystem haben wir dazu die Hausmaus verwendet. Tiere wurden entweder gemäss einem typische Wintertag (d.h. nur 8 h Tageslänge), einem typischen Labortag (d.h. 12 h Tageslänge), oder einem typischen Sommertag (d.h. 16 h Tageslänge) gehalten, und dann ihr Metabolismus und ihre Physiologie untersucht. Eine typische Uhr besteht aus drei Komponenten: einem zentralen Oszillator, der den Rhythmus generiert, und jeweils einer Inputfunktion, die die Phase der Uhr mit der Umwelt in Einklang bringt, und einer Outputfunktion, die rhythmische Prozesse regulieren kann. Basierend auf den Daten, die wir in unseren Experimenten gemessen haben, konnten wir ein regulatorisches Modell aufstellen, welches die Zusammenhänge der Veränderungen an den verschiedenen Tagen beschreibt. Unser Modell enthält einige zentrale Komponenten, die den Rhythmus generieren. Basierend auf den Daten vermuten wir, dass der Oszillator der Leber eine einzelne Inputfunktion besitzt. Allerdings muss dieser Befund noch experimentell überprüft werden. Unser Modell berücksichtigt weiterhin alle drei bekannten Outputfunktionen des zirkadianen Oszillators. Dies ist wichtig, da wir im nächsten Schritt das Modell schrittweise vergrössern wollen, um alle regulatorischen Prozesse in der Leber verstehen zu können. Zur Zeit sind wir dabei, das regulatorische Modell durch ein mathematisches Modell zu beschreiben um die flexiblen Punkte in der zirkadianen Uhr zu finden. Allerdings ist dieses Modell sehr aufwendig und muss noch optimiert werden.

Wissenschaftlicher und gesellschaftlicher Kontext

Das Projekt befasste sich mit Grundlagenforschung. In den letzten Jahren haben sich Therapien etabliert, die die täglichen Veränderungen im Metabolismus oder in der Physiologie auszunutzen versuchen. Die Idee dahinter ist, dass sich auf diese Weise die Wirkungsweise eines Medikamentes verstärken, oder die Nebenwirkungen verringert werden können. Die Leber spielt dabei eine wichtige Rolle, da sie die Entgiftungsvorgänge im Körper reguliert. Allerdings berücksichtigen viele dieser Therapien nicht die Veränderungen der äusseren Tageslänge und deren Einfluss auf die Leberfunktion. Deshalb werden wir weiterforschen um diese Veränderungen zu verstehen.

 

Direct link to Lay Summary Last update: 12.05.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Altered Sleep Homeostasis in Rev-erbα Knockout Mice.
Mang Géraldine M, La Spada Francesco, Emmenegger Yann, Chappuis Sylvie, Ripperger Jürgen A, Albrecht Urs, Franken Paul (2016), Altered Sleep Homeostasis in Rev-erbα Knockout Mice., in Sleep, 39(3), 589-601.
Liver-derived ketone bodies are necessary for food anticipation.
Chavan Rohit, Feillet Céline, Costa Sara S Fonseca, Delorme James E, Okabe Takashi, Ripperger Jürgen A, Albrecht Urs (2016), Liver-derived ketone bodies are necessary for food anticipation., in Nature communications, 7, 10580-10580.
REV-ERBα influences the stability and nuclear localization of the glucocorticoid receptor.
Okabe Takashi, Chavan Rohit, Fonseca Costa Sara S, Brenna Andrea, Ripperger Jürgen A, Albrecht Urs (2016), REV-ERBα influences the stability and nuclear localization of the glucocorticoid receptor., in Journal of cell science, 129(21), 4143-4154.
Grab the wiggly tail: new insights into the dynamics of circadian clocks.
Hui Ka Yi, Ripperger Jürgen A (2015), Grab the wiggly tail: new insights into the dynamics of circadian clocks., in Nature structural & molecular biology, 22(6), 435-6.
Impact of the circadian clock on the aging process.
Fonseca Costa Sara S, Ripperger Jürgen A (2015), Impact of the circadian clock on the aging process., in Frontiers in neurology, 6, 43-43.
Mice lacking circadian clock components display different mood-related behaviors and do not respond uniformly to chronic lithium treatment.
Schnell Anna, Sandrelli Federica, Ranc Vaclav, Ripperger Jürgen A, Brai Emanuele, Alberi Lavinia, Rainer Gregor, Albrecht Urs (2015), Mice lacking circadian clock components display different mood-related behaviors and do not respond uniformly to chronic lithium treatment., in Chronobiology international, 32(8), 1075-89.
Rev-erbα modulates the hypothalamic orexinergic system to influence pleasurable feeding behaviour in mice.
Feillet Céline A, Bainier Claire, Mateo Maria, Blancas-Velázquez Aurea, Salaberry Nora L, Ripperger Jürgen A, Albrecht Urs, Mendoza Jorge (2015), Rev-erbα modulates the hypothalamic orexinergic system to influence pleasurable feeding behaviour in mice., in Addiction biology, PMID: 2663.
A specific role for the REV-ERBα-controlled L-Type Voltage-Gated Calcium Channel CaV1.2 in resetting the circadian clock in the late night.
Schmutz Isabelle, Chavan Rohit, Ripperger Jürgen A, Maywood Elizabeth S, Langwieser Nicole, Jurik Angela, Stauffer Anja, Delorme James E, Moosmang Sven, Hastings Michael H, Hofmann Franz, Albrecht Urs (2014), A specific role for the REV-ERBα-controlled L-Type Voltage-Gated Calcium Channel CaV1.2 in resetting the circadian clock in the late night., in Journal of biological rhythms, 29(4), 288-98.
The nuclear receptor REV-ERBα regulates Fabp7 and modulates adult hippocampal neurogenesis.
Schnell Anna, Chappuis Sylvie, Schmutz Isabelle, Brai Emanuele, Ripperger Jürgen A, Schaad Olivier, Welzl Hans, Descombes Patrick, Alberi Lavinia, Albrecht Urs (2014), The nuclear receptor REV-ERBα regulates Fabp7 and modulates adult hippocampal neurogenesis., in PloS one, 9(6), 99883-99883.
NONO couples the circadian clock to the cell cycle
Kowalska Elzbieta, Ripperger Juergen A., Hoegger Dominik C., Bruegger Pascal, Buch Thorsten, Birchler Thomas, Mueller Anke, Albrecht Urs, Contaldo Claudio, Brown Steven A. (2013), NONO couples the circadian clock to the cell cycle, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110(5), 1592-1599.
PER2 promotes glucose storage to liver glycogen during feeding and acute fasting by inducing Gys2 PTG and G L expression.
Zani Fabio, Breasson Ludovic, Becattini Barbara, Vukolic Ana, Montani Jean-Pierre, Albrecht Urs, Provenzani Alessandro, Ripperger Juergen A, Solinas Giovanni (2013), PER2 promotes glucose storage to liver glycogen during feeding and acute fasting by inducing Gys2 PTG and G L expression., in Molecular metabolism, 2(3), 292-305.
Role of the circadian clock gene Per2 in adaptation to cold temperature.
Chappuis Sylvie, Ripperger Jürgen Alexander, Schnell Anna, Rando Gianpaolo, Jud Corinne, Wahli Walter, Albrecht Urs (2013), Role of the circadian clock gene Per2 in adaptation to cold temperature., in Molecular metabolism, 2(3), 184-93.
Circadian rhythms govern cardiac repolarization and arrhythmogenesis.
Jeyaraj Darwin, Haldar Saptarsi M, Wan Xiaoping, McCauley Mark D, Ripperger Jürgen A, Hu Kun, Lu Yuan, Eapen Betty L, Sharma Nikunj, Ficker Eckhard, Cutler Michael J, Gulick James, Sanbe Atsushi, Robbins Jeffrey, Demolombe Sophie, Kondratov Roman V, Shea Steven A, Albrecht Urs, Wehrens Xander H T, Rosenbaum David S, Jain Mukesh K (2012), Circadian rhythms govern cardiac repolarization and arrhythmogenesis., in Nature, 483(7387), 96-9.
Distinct Roles of DBHS Family Members in the Circadian Transcriptional Feedback Loop
Kowalska Elzbieta, Ripperger Juergen A., Muheim Christine, Maier Bert, Kurihara Yasuyuki, Fox Archa H., Kramer Achim, Brown Steven A. (2012), Distinct Roles of DBHS Family Members in the Circadian Transcriptional Feedback Loop, in MOLECULAR AND CELLULAR BIOLOGY, 32(22), 4585-4594.
Klf15 orchestrates circadian nitrogen homeostasis.
Jeyaraj Darwin, Scheer Frank A J L, Ripperger Jürgen A, Haldar Saptarsi M, Lu Yuan, Prosdocimo Domenick A, Eapen Sam J, Eapen Betty L, Cui Yingjie, Mahabeleshwar Ganapathi H, Lee Hyoung-gon, Smith Mark A, Casadesus Gemma, Mintz Eric M, Sun Haipeng, Wang Yibin, Ramsey Kathryn M, Bass Joseph, Shea Steven A, Albrecht Urs, Jain Mukesh K (2012), Klf15 orchestrates circadian nitrogen homeostasis., in Cell metabolism, 15(3), 311-23.
REV-ERB-erating nuclear receptor functions in circadian metabolism and physiology
Ripperger Juergen A., Albrecht Urs (2012), REV-ERB-erating nuclear receptor functions in circadian metabolism and physiology, in CELL RESEARCH, 22(9), 1319-1321.
The circadian clock component PERIOD2: from molecular to cerebral functions.
Ripperger Jürgen A, Albrecht Urs (2012), The circadian clock component PERIOD2: from molecular to cerebral functions., in Progress in brain research, 199, 233-45.
The role of clock genes and rhythmicity in the liver
Schmutz I., Albrecht U., Ripperger J. A. (2012), The role of clock genes and rhythmicity in the liver, in MOLECULAR AND CELLULAR ENDOCRINOLOGY, 349(1), 38-44.
The role of clock genes and rhythmicity in the liver.
Schmutz I, Albrecht U, Ripperger J A (2012), The role of clock genes and rhythmicity in the liver., in Molecular and cellular endocrinology, 349(1), 38-44.
Perfect timing: epigenetic regulation of the circadian clock.
Ripperger Jürgen A, Merrow Martha (2011), Perfect timing: epigenetic regulation of the circadian clock., in FEBS letters, 585(10), 1406-11.
The circadian molecular clock creates epidermal stem cell heterogeneity.
Janich Peggy, Pascual Gloria, Merlos-Suárez Anna, Batlle Eduard, Ripperger Jürgen, Albrecht Urs, Cheng Hai-Ying M, Obrietan Karl, Di Croce Luciano, Benitah Salvador Aznar (2011), The circadian molecular clock creates epidermal stem cell heterogeneity., in Nature, 480(7376), 209-14.
The daily rhythm of mice
Ripperger Juergen A., Jud Corinne, Albrecht Urs (2011), The daily rhythm of mice, in FEBS LETTERS, 585(10), 1384-1392.
The daily rhythm of mice.
Ripperger Jürgen A, Jud Corinne, Albrecht Urs (2011), The daily rhythm of mice., in FEBS letters, 585(10), 1384-92.

Collaboration

Group / person Country
Types of collaboration
Riken CDB Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Université de Genève Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Universität Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Charité Berlin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EBRS Talk given at a conference Role of circadian PAR-bZip transcription factors within the mammalian circadian clock 18.08.2013 München, Germany Ripperger Jürgen A.;
Gordon Conference Chronobiology Talk given at a conference Role of circadian transcription factors in aging 14.07.2013 Newport, United States of America Ripperger Jürgen A.;
Gordon Conference Chronobiology Talk given at a conference Impact of dynamic histone H3.3 exchange on the mammalian circadian oscillator 12.06.2011 Lucca, Italy, Italy Ripperger Jürgen A.;


Self-organised

Title Date Place
2nd Swiss Chronobiology Meeting 05.09.2013 Fribourg, Switzerland
1st Swiss Chronobiology Meeting 28.08.2012 Fribourg, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Sich Zeit lassen. Wenn die innere Uhr aus dem Takt gerät... Update 2011 / 03 German-speaking Switzerland 2011

Associated projects

Number Title Start Funding scheme
120407 Analysis of ciradian chromatin methylation 01.05.2008 Project funding (Div. I-III)
152792 Age-related changes of the liver circadian oscillator 01.04.2014 Project funding (Div. I-III)

Abstract

2.1 SUMMARY: Adjustment of the mouse liver transcriptome to the photoperiod2.1.1 BACKGROUNDRhythmic transcription (circadian and/or food driven) is quite prominent in the liver. As a speculation, these rhythms synchronize the hepatic metabolism with the environment to enhance fitness. Although the liver is not directly light sensitive, the photoperiod (i.e. the day/night length ratio) affects the expression phase of hepatic circadian oscillator genes. Interestingly, two circadian genes have been identified in the liver, which in response to the photoperiod display different phase adjustments compared to the core oscillator components. In the case of these genes, special phase adjustment mechanisms may be important for the proper function of their gene products. However, it is unknown, how circadian genes, and all the other rhythmic genes in the liver, change their phase according to the photoperiod. Using biochemical and ultra-deep-sequencing approaches, we would like to understand I) the interplay between circadian oscillators and these adjustment processes; and II) the adjustment of the transcriptional networks to different photoperiods. We expect that our experiments will provide a comprehensive picture of the adjustment processes and the concomitant changes in the liver metabolism.2.1.2 WORKING HYPOTHESISSpecific transcriptional mechanisms adjust the hepatic transcriptome to the photoperiod.2.1.3 SPECIFIC AIMSI. Analysis of the relationship of circadian oscillators and adjustment mechanisms. We systematically analyze the circadian oscillator of knock-out mouse strains in different photoperiods. First, we measure their behavior and food uptake under these conditions. Secondly, we analyze the adjustment of their liver circadian oscillators to different photoperiods. This systematic analysis provides insights to understand the interplay between the circadian oscillator and the adjustment processes. To monitor the biological relevance of the adjustment processes, we will analyze the metabolic and detoxification potential of the liver using cytoplasm or isolated microsomes. In particular, we investigate glucose homeostasis and some detoxification pathways for anti-cancer drugs.II. Analysis of the mouse liver transcriptome in different photoperiods. We employ a global sequencing approach to analyze and compare the entire mouse liver transcriptome in different photoperiods. An adapted 5’-SAGE method allows identifying the peaks of rhythmic gene expression, the approximate position of their promoters, and outliers, whose phase adjustment deviates from the other genes. Specific transcription factors involved in adjustment or uncoupling processes emerge by motif scans. The importance of an identified transcriptional regulator to affect the phase of a group of target genes can then be verified in vitro by knock-down and over-expression experiments using hepatoma cells or primary hepatocytes and reporter genes driven by the identified promoters.2.1.4 SIGNIFICANCEOur experiments aim to get a coherent picture of the adjustment processes that occur in the liver transcriptome as a response to the changing photoperiod. Given that this organ is the major detoxification organ in mammals, it is necessary to understand these phase adjustments to optimally exploit the potential of e.g. chronotherapeutic treatments.
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