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The mammalian clock component PERIOD2 coordinates circadian output by interaction with nuclear receptors
Open accessAbstract
Mammalian circadian clocks provide a temporal framework to synchronize biological functions. To obtain robust rhythms with a periodicity of about a day, these clocks use molecular oscillators consisting of two interlocked feedback loops. The core loop generates rhythms by transcriptional repression via the Period (PER) and Cryptochrome (CRY) proteins, whereas the stabilizing loop establishes roughly antiphasic rhythms via nuclear receptors. Nuclear receptors also govern many pathways that affect metabolism and physiology. Here we show that the core loop component PER2 can coordinate circadian output with the circadian oscillator. PER2 interacts with nuclear receptors including PPARalpha and REV-ERBalpha and serves as a coregulator of nuclear receptor-mediated transcription. Consequently, PER2 is rhythmically bound at the promoters of nuclear receptor target genes in vivo. In this way, the circadian oscillator can modulate the expression of nuclear receptor target genes like Bmal1, Hnf1alpha, and Glucose-6-phosphatase. The concept that PER2 may propagate clock information to metabolic pathways via nuclear receptors adds an important facet to the clock-dependent regulation of biological networks.
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“Per2 mutant mice show reduced fasting glycemia, a loss of rhythmic glycogen accumulation in the liver, elevated plasma insulin levels and impaired gluconeogenesis [20–22]”
From Circadian control of glucose metabolism (2014) · cites this paper as [20]
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BackgroundInfluentialPER2 controls lipid metabolism by direct regulation of PPARγ
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“[20] Per2 Decreased”
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Daily eating patterns and their impact on health and disease
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Delay in Feedback Repression by Cryptochrome 1 Is Required for Circadian Clock Function
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“…interaction (Vielhaber et al. 2000; Lee et al. 2004); a proline-rich region; and an LXXLL nuclear receptor interaction motif (Albrecht et al. 2007; Schmutz et al. 2010) followed by a 100-amino-acid stretch known to be the primary CRY-interacting domain (Eide et al. 2002; Yagita et al. 2002; Chen…”
BackgroundCircadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals
Kumar Jha, P., Challet, E., & Kalsbeek, A. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.01.024 · Cited by 235
“…et al. (2011) Per2 Global Brdm1 mutation Reduced fasting glycemia and altered glycogen storage Zani et al. (2013) Global Brdm1 mutation Hypoglycemia Schmutz et al. (2010) Global Brdm1 mutation Hyperinsulinemia, increased glucose tolerance and insulin sensitivity Zhao et al. (2012) Global knock-out…”
InfluentialMammalian circadian clock and metabolism – the epigenetic link
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“with several nuclear receptors (Schmutz et al., 2010) and to directly regulate PPAR function (Grimaldi et al.”
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Tahara, Y., & Shibata, S. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.8 · Cited by 238
PPARs Integrate the Mammalian Clock and Energy Metabolism
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“Based on indirect evidence, it has been previously reported that PER2 can up-regulate gene transcription by interacting with another transcription factor (25) or by removing CRY from CLOCK–BMAL1 (20).”
BackgroundMachine Learning Helps Identify CHRONO as a Circadian Clock Component
Anafi, R. C., Lee, Y., Sato, T. K., Venkataraman, A., Ramanathan, C., Kavaklı, İ. H., Hughes, M. E., Baggs, J. E., Growe, J., Liu, A. C., et al. (2014) · PLoS Biology · doi:10.1371/journal.pbio.1001840 · Cited by 152
“PER2 not only binds with cryptochromes but also interacts with nuclear receptors NR1D1 and RORA [66].”
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Hwang‐Verslues, W. W., & Sladek, F. M. (2010) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2010.08.010 · Cited by 148
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“Albrecht and colleagues [167,179], demonstrated physical and functional associations between the PER2 protein and several nuclear receptors including REV-ERBa, and, to a lesser extent, the RORs.”
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“For example, the nuclear receptors NURR1 and TRa, among others physically interact with the PER2 protein [200].”
BackgroundBiochemical Analysis of the Canonical Model for the Mammalian Circadian Clock
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“An interaction motif for NRs, LXXLL (58), is found on the βE-strand of PAS-A in all mPERs, although the Ncap occludes this region to various extents in the respective structures.”
Role of the circadian clock gene Per2 in adaptation to cold temperature
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Berthier, A., Johanns, M., Zummo, F. P., Lefebvre, P., & Staels, B. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166097 · Cited by 125
“In murine liver, rhythmic interaction of PER2 with PPARα bound to PPAR target gene promoters such as Arntl (BMAL1), Hnf1a and G6pc , results in a cyclical transregulation of crucial metabolic genes [117].”
BackgroundPeripheral Circadian Oscillators in Mammals
Brown, S. A., & Azzi, A. (2013) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-25950-0_3 · Cited by 124
“In a separate loop, the nuclear receptor ROR and REV-ERB proteins activate and repress the Bmal1 gene, respectively.”
BackgroundInfluentialLiver-derived ketone bodies are necessary for food anticipation
Chavan, R., Feillet, C. A., Costa, S. S., Delorme, J. E., Okabe, T., Ripperger, J. A., & Albrecht, U. (2016) · Nature Communications · doi:10.1038/ncomms10580 · Cited by 127
Spatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology
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Cheon, S., Park, N., Cho, S., & Kim, K. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt307 · Cited by 123
“Direct interactions between PER2 and various nuclear receptors, including HNF4a, REV-ERBa and PPARa, enable the circadian oscillation of glucose and lipid metabolism (22).”
BackgroundInteractions between metabolism and circadian clocks: reciprocal disturbances
Delezie, J., & Challet, É. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06246.x · Cited by 124
Circadian Metabolism: From Mechanisms to Metabolomics and Medicine
Brown, S. A. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.03.015 · Cited by 122
CRY1/2 Selectively Repress PPARδ and Limit Exercise Capacity
Jordan, S. D., Kriebs, A., Vaughan, M. E., Duglan, D., Fan, W., Henriksson, E., Huber, A., Papp, S. J., Nguyen, M., Afetian, M. E., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.002 · Cited by 115
Ramanathan, C., Xu, H., Khan, S. K., Shen, Y., Gitis, P. J., Welsh, D. K., Hogenesch, J. B., & Liu, A. C. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004244 · Cited by 110
“, Nr1d1 and Nr1d2) than on ROREcontaining genes such as Bmal1, E4bp4, and Cry1 (Figure 5C), in line with the notion that the PERs can directly and indirectly affect Bmal1 transcription [65,66].”
BackgroundNuclear receptors rock around the clock
Zhao, X., Cho, H., Yu, R. T., Atkins, A. R., Downes, M., & Evans, R. M. (2014) · EMBO Reports · doi:10.1002/embr.201338271 · Cited by 109
“Physiologically, PER2 and REV-ERB a appear to coordinately regulate the expression of liver genes important for gluconeogenesis and glucose metabolism [49].”
The Nuclear Receptor REV-ERBα Regulates Fabp7 and Modulates Adult Hippocampal Neurogenesis
Schnell, A., Chappuis, S., Schmutz, I., Brai, E., Ripperger, J. A., Schaad, O., Welzl, H., Descombes, P., Alberi, L. A., & Albrecht, U. (2014) · PLoS ONE · doi:10.1371/journal.pone.0099883 · Cited by 108
“Empty pGL3-vector and Bmal1 promoter region cloned into pGL3 [39], were used as negative and positive controls, respectively.”
MethodInfluentialNutrient sensing and the circadian clock
Peek, C. B., Ramsey, K. M., Marcheva, B., & Bass, J. T. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.02.003 · Cited by 109
“Intriguingly, it has been reported that in addition to being regulated by the clock, SIRT1 also regulates clock function itself (28– 30) through deacetylation of both BMAL1 and PER2, leading to altered CLOCK/BMAL1 transcriptional activity [30–32] (figure 1).”
BackgroundInfluentialKriebs, A., Jordan, S. D., Soto, E., Henriksson, E., Sandate, C. R., Vaughan, M. E., Chan, A. B., Duglan, D., Papp, S. J., Huber, A., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1704955114 · Cited by 108
Circadian autophagy rhythm: a link between clock and metabolism?
Ma, D., Li, S., Molusky, M. M., & Lin, J. D. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.03.004 · Cited by 106
“The expression of many NHRs exhibits circadian regulation [20], some of which also directly interact with clock proteins [21, 22], potentially synchronizing the expression of clock and metabolic genes.”
BackgroundGenomic Convergence among ERRα, PROX1, and BMAL1 in the Control of Metabolic Clock Outputs
Dufour, C. R., Levasseur, M.-P., Pham, N. H. H., Eichner, L. J., Wilson, B. J., Charest-Marcotte, A., Duguay, D., Poirier-Héon, J.-F., Cermakian, N., & Giguère, V. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002143 · Cited by 107
“Third, PER2 has recently been shown to propagate clock information to metabolic genes by directly interacting with and acting as a coregulator of nuclear receptor-mediated transcription [23].”
BackgroundClock gene variants in mood and anxiety disorders
Partonen, T. (2012) · Journal of Neural Transmission · doi:10.1007/s00702-012-0810-2 · Cited by 101
“Here, the PER2 protein may have a persuading role, as its binding at the promoters of nuclear receptor target genes, such as the NR1D1 gene, oscillates and thereby propagates the circadian information to metabolic pathways (Schmutz et al. 2010).”
BackgroundZmrzljak, U. P., & Rozman, D. (2012) · Chemical Research in Toxicology · doi:10.1021/tx200538r · Cited by 97
Circadian regulation of liver function: from molecular mechanisms to disease pathophysiology
Bolshette, N. B., Ibrahim, H., Reinke, H., & Asher, G. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00792-1 · Cited by 109
“For instance, PPARα regulates Bmal1 , Per2 and Per3 expression in mouse liver 126,127 .”
BackgroundWang, T., Wang, Z., Yang, P., Xia, L., Zhou, M., Wang, S., Du, J., & Zhang, J. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.9 · Cited by 96
“[39] [40] [41] [42] [43] PER3 interacts with PPAR-γ via an N-terminal region including both PAS domains and a preceding predicted helix-loop-helix motif.”
BackgroundChrono-biology, Chrono-pharmacology and Chrono-nutrition
Tahara, Y., & Shibata, S. (2014) · Journal of Pharmacological Sciences · doi:10.1254/jphs.13r06cr · Cited by 94
Nuclear receptor signal transduction in C. elegans
Antebi, A. (2015) · WormBook · doi:10.1895/wormbook.1.64.2 · Cited by 93
“It is noteworthy that several mammalian NRs bind to and are inhibited by PER2, suggesting a conserved interaction between NRs and components of the circadian clock (Grimaldi et al., 2010; Schmutz et al., 2010).”
BackgroundRipperger, J. A., Jud, C., & Albrecht, U. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.02.027 · Cited by 98
The Circadian Clock in Oral Health and Diseases
Papagerakis, S. M., Zheng, L., Schnell, S. D., Sartor, M., Somers, E. C., Marder, W., McAlpin, B. R., Kim, D. W., McHugh, J. B., & Papagerakis, P. (2013) · Journal of Dental Research · doi:10.1177/0022034513505768 · Cited by 95
“For example, PER interaction with REV-ERBa modulates transcription of gluconeogenic factor G6pase (Schmutz et al., 2010).”
Emerging Models for the Molecular Basis of Mammalian Circadian Timing
Gustafson, C. L., & Partch, C. L. (2014) · Biochemistry · doi:10.1021/bi500731f · Cited by 91
Circadian rhythms in the blood–brain barrier: impact on neurological disorders and stress responses
Schurhoff, N. A., & Toborek, M. J. (2023) · Molecular Brain · doi:10.1186/s13041-023-00997-0 · Cited by 95
“PER2 synchronizes this loop by interacting with REV-ERBα that affects both positive and negative elements [61].”
BackgroundThe circadian mutation PER2S662G is linked to cell cycle progression and tumorigenesis
Gu, X., Xing, L., Shi, G., Liu, Z., Wang, X., Qu, Z., Wu, X., Dong, Z., Gao, X., Liu, G., et al. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.103 · Cited by 92
“This assumption is supported by a recent study by Isabelle Schmutz et al.5 demonstrating that PER2 coordinates circadian output by interacting with NR1D1.”
Circadian oscillator proteins across the kingdoms of life: structural aspects
Saini, R. V., Jaskólski, M., & Davis, S. J. (2019) · BMC Biology · doi:10.1186/s12915-018-0623-3 · Cited by 92
Filiano, A. N., Millender-Swain, T., Johnson, R., Young, M. E., Gamble, K. L., & Bailey, S. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071684 · Cited by 92
“PER2, another core clock protein, interacts with the PPARa protein and influences the transcription of metabolic genes in liver [50].”
BackgroundCircadian Clocks and Mood-Related Behaviors
Albrecht, U. (2013) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-25950-0_9 · Cited by 86
Circadian Rhythm Gene Period 3 Is an Inhibitor of the Adipocyte Cell Fate
Costa, M. J. D. C., So, A. Y., Kaasik, K., Krueger, K. C., Pillsbury, M. L., Fu, Y., Ptáček, L. J., Yamamoto, K. R., & Feldman, B. J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.164558 · Cited by 83
The circadian clock, metabolism and obesity
Albrecht, U. (2017) · Obesity Reviews · doi:10.1111/obr.12502 · Cited by 84
“This interaction leads to rhythmic modulation of promoters of nuclear receptor target genes in vivo by PER2, like Bmal1, Hnf1α and Glucose-6-phosphatase (21).”
BackgroundNuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks
Qu, M., Duffy, T., Hirota, T., & Kay, S. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1816411115 · Cited by 85
Endocrine regulation of circadian physiology
Tsang, A. H. K., Astiz, M., Friedrichs, M., & Oster, H. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0051 · Cited by 86
Potential Roles of Dec and Bmal1 Genes in Interconnecting Circadian Clock and Energy Metabolism
Sato, F., Kohsaka, A., BHAWAL, U. K., & Muragaki, Y. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030781 · Cited by 85
“PER2 also interacts with the PPARα protein through its LXXLL motifs [117].”
BackgroundThe PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology
Oh, H. Y. P., Visvalingam, V., & Wahli, W. (2019) · The FASEB Journal · doi:10.1096/fj.201802681rr · Cited by 79
The emerging roles of lipids in circadian control
Adamovich, Y., Aviram, R., & Asher, G. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2014.11.013 · Cited by 78
“Interestingly, PPARα binding on Bmal1 gene regulatory region overlaps with PER2 binding and correlates with activation of Bmal1 expression [61].”
BackgroundZani, F., Breasson, L., Becattini, B., Vukolic, A., Montani, J.-P., Albrecht, U., Provenzani, A., Ripperger, J. A., & Solinas, G. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2013.06.006 · Cited by 75
Circadian Clocks and Metabolism: Implications for Microbiome and Aging
Paschos, G. K., & FitzGerald, G. A. (2017) · Trends in Genetics · doi:10.1016/j.tig.2017.07.010 · Cited by 79
“PER2 interacts directly with Peroxisome proliferator-activated receptor alpha (PPARα) to rhythmically modulate its target gene G6pc encoding glucose-6-phosphatase [34].”
BackgroundCREBH Couples Circadian Clock With Hepatic Lipid Metabolism
Zheng, Z., Kim, H., Qiu, Y., Chen, X., Méndez, R., Dandekar, A. P., Zhang, X., Zhang, C., Liu, A. C., Yin, L., et al. (2016) · Diabetes · doi:10.2337/db16-0298 · Cited by 76
“Circadian transcriptional regulators may interact with local transcription factors or nuclear receptors to control the circadian output of gene expression (26).”
BackgroundCircadian clock dysfunction in human omental fat links obesity to metabolic inflammation
Maury, E., Navez, B., & Brichard, S. M. (2021) · Nature Communications · doi:10.1038/s41467-021-22571-9 · Cited by 77
SRC-2 Is an Essential Coactivator for Orchestrating Metabolism and Circadian Rhythm
Stashi, E., Lanz, R. B., Mao, J., Michailidis, G. C., Zhu, B., Kettner, N. M., Putluri, N., Reineke, E. L., Reineke, L. C., Dasgupta, S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.01.027 · Cited by 74
“Given that many NRs demonstrate temporal rhythms and that SRC-2 occupancy of the cistrome at ZT4 identifies approximately twice as many peaks as at ZT18, we explored the diurnal expression of SRC-2 using high-density quantitative PCR (hdqPCR) across several key metabolic tissues (i.e., liver, BAT, WAT, heart, skeletal…”
BackgroundInfluentialBellet, M. M., Masri, S., Astarita, G., Sassone‐Corsi, P., Fazia, M. A. D., & Servillo, G. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.737114 · Cited by 78
“Indeed, under high-fat diet Sirt1 LKO mice accumulate an excessive amount of fat due to a defect in FA betaoxidation dependent on PPAR (28), a nuclear receptor whose expression and transcriptional activity is directly regulated by the circadian system (31).”
BackgroundKucera, N., Schmalen, I., Hennig, S., Öllinger, R., Strauss, H. M., Grudziecki, A., Wieczorek, C. M., Kramer, A., & Wolf, E. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113280109 · Cited by 74
“Since the mutation of the mPER1 335PCCLL coactivator motive to the mPER2 sequence (LCCLL) did not restore mPER1 binding to REV-ERB (23), additional regions ormolecular features ofmPER2 appear to be required.”
BackgroundInfluentialPER1 Phosphorylation Specifies Feeding Rhythm in Mice
Liu, Z., Huang, M., Wu, X., Shi, G., Xing, L., Dong, Z., Qu, Z., Yan, J., Yang, L., Panda, S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.032 · Cited by 73
“A recent study demonstrated that PER2 rather than PER1 integration with various nuclear receptors provides an explanation for the functional differences between these two PER proteins (Schmutz et al., 2010).”
Bonney, S. K., Kominsky, D., Brodsky, K. S., Eltzschig, H. K., Walker, L. A., & Eckle, T. D. L. G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071493 · Cited by 74
“Although Per2 cannot bind to DNA itself, it has been shown that Per2 is able to act as co- regulator of transcription [48].”
BackgroundFatty-Acid Binding Proteins Modulate Sleep and Enhance Long-Term Memory Consolidation in Drosophila
Gerstner, J. R., Vanderheyden, W. M., Shaw, P. J., Landry, C. F., & Yin, J. C. P. (2011) · PLoS ONE · doi:10.1371/journal.pone.0015890 · Cited by 71
“Since PPARs are involved in the circadian clockwork in various tissues and cell types [63-66], these data provide additional evidence for Fabp signaling in gating temporal and memory-enhancing processes.”
BackgroundRegulation of αENaC expression by the circadian clock protein Period 1 in mpkCCDc14 cells
Gumz, M. L., Cheng, K., Lynch, I. J., Stow, L. R., Greenlee, M. M., Cain, B. D., & Wingo, C. S. (2010) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2010.09.003 · Cited by 70
“Per2 was recently shown to interact with nuclear receptors PPARα and RevERBα [38]).”
Rossetti, S., Esposito, J., Corlazzoli, F., Gregorski, A., & Sacchi, N. (2012) · Cell Cycle · doi:10.4161/cc.11.2.18792 · Cited by 73
Annayev, Y., Adar, S., Chiou, Y., Lieb, J. D., Sancar, A., & Ye, R. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.534651 · Cited by 73
Metadata
- Authors
- Schmutz, I., Ripperger, J. A., Baeriswyl-Aebischer, S., & Albrecht, U.
- Affiliations
- University of Fribourg (CH)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-02-15
- Volume
- 24
- Issue
- 4
- Pages
- 345-357
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2816734
- OpenAlex
- W2122503953
- Cited by
- 361
- References
- 64
- Citations by year
- 2026: 6 · 2025: 22 · 2024: 12 · 2023: 17 · 2022: 19 · 2021: 26 · 2020: 14 · 2019: 21 · 2018: 14 · 2017: 21 · 2016: 23 · 2015: 23 · 2014: 37 · 2013: 30 · 2012: 35
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Light effects on plants
- Keywords
- Per2, circadian clock, nuclear receptors, PPARα, NR1D1, co-regulation, transcriptional repression, Bmal1, HNF1A, glucose-6-phosphatase, promoter binding
- MeSH terms
- Animals, Circadian Rhythm, Gene Expression Regulation, Glucose, Liver, Promoter Regions, Genetic, Protein Binding, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Amino Acid Motifs, NIH 3T3 Cells, PPAR alpha, Mice, ARNTL Transcription Factors, Period Circadian Proteins, Nuclear Receptor Subfamily 1, Group D, Member 1
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