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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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Dynamics of the circadian clock protein PERIOD2 in living cells
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“The nuclear-receptor-binding motif of PER2 is responsible for low nuclear mobility PER2 does not possess a DNA-binding domain but can bind indirectly to DNA through the transcription factors CLOCK– BMAL1 (Sangoram et al., 1998), as well as the nuclear receptors REV-ERBa (also known as NR1D1) and PPARa (Schmutz et al.,…”
InfluentialCircadian regulation of transporter expression and implications for drug disposition
Pácha, J., Balounová, K., & Soták, M. (2020) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2021.1868438 · Cited by 22
“receptor PPARα was observed to bind to the promoter region of the HNF4α-controlled Hnf1α gene and changed the activity of the target gene [108]; HNF1α is a central regulator of many”
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“The interaction of Per2 with NRs seems to require an NR box in the N-terminus of Per2 that is not conserved in Per1 or Per3 (Schmutz et al., 2010), and the interaction of Per3 with PPARγ also requires the N-terminal domain of Per3 (Costa et al.”
BackgroundInfluentialThe Circadian Regulation of Nutrient Metabolism in Diet-Induced Obesity and Metabolic Disease
Woodie, L. N., Oral, K. T., Krusen, B. M., & Lazar, M. A. (2022) · Nutrients · doi:10.3390/nu14153136 · Cited by 24
“Furthermore, PER out of complex with CRY will inhibit REV-ERBs’ repression of Bmal1 [40] (Figure 1b).”
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Kohsaka, A., Waki, H., Cui, H., Gouraud, S. S., & Maeda, M. (2012) · Endocrine Journal · doi:10.1507/endocrj.ej12-0057 · Cited by 21
Transcription Factor Interactions in Genomic Nuclear Receptor Function
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REV-ERBα regulates Fgf21 expression in the liver via hepatic nuclear factor 6
Chavan, R., Preitner, N., Okabe, T., Mansencal-Strittmatter, L., Xu, C., Ripperger, J. A., Pitteloud, N., & Albrecht, U. (2016) · Biology Open · doi:10.1242/bio.021519 · Cited by 22
“The livers of mice were homogenized in 1× phosphate-buffered saline supplemented with 1% formaldehyde, incubated for 5 min at room temperature, and nuclei and chromatin prepared according to (Schmutz et al., 2010).”
InfluentialNuclear Receptors and AMPK: Resetting MetabolismPreprint
Fan, W., Downes, M., Atkins, A. R., Yu, R. T., & Evans, R. M. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2012.76.010470 · Cited by 20
“Other NRs such as HNF4, TRa, NURR1, and RORs have also been shown to physically interact with PER2, although their direct involvement in the regulation of circadian rhythm has not been established (Schmutz et al. 2010).”
BackgroundSex-dependent effects of chronic jet lag on circadian rhythm and metabolism in mice
Ma, T., Matsuo, R., Kurogi, K., Miyamoto, S., Morita, T., Shinozuka, M., Taniguchi, F., Ikegami, K., & Yasuo, S. (2024) · Biology of Sex Differences · doi:10.1186/s13293-024-00679-z · Cited by 22
Targeting circadian PER2 as therapy in myocardial ischemia and reperfusion injury
Oyama, Y., Walker, L. A., & Eckle, T. D. L. G. (2021) · Chronobiology International · doi:10.1080/07420528.2021.1928160 · Cited by 19
“bolism in white adipose tissue and the liver (Schmutz et al. 2010; Grimaldi et al. 2010).”
BackgroundInfluentialDifferential effects of SUMO1 and SUMO2 on circadian protein PER2 stability and function
Chen, L.-C., Hsieh, Y.-L., Tan, G. Y. T., Kuo, T.-Y., Chou, Y., Hsu, P., & Hwang‐Verslues, W. W. (2021) · Scientific Reports · doi:10.1038/s41598-021-93933-y · Cited by 22
Redox Homeostasis in Ocular Tissues: Circadian Regulation of Glutathione in the Lens?
Lim, J. C.-H., Suzuki‐Kerr, H., Nguyen, T. X., Lim, C. J. J., & Poulsen, R. C. (2022) · Antioxidants · doi:10.3390/antiox11081516 · Cited by 21
“CLOCK/BMAL1 activates the transcription of period (Per) and cryptochrome (Cry) genes, and, in turn, PER and CRY proteins inhibit their own expression by repressing CLOCK/BMAL1 activity [32].”
BackgroundShibata, S., & Tahara, Y. (2014) · The Journal of Physical Fitness and Sports Medicine · doi:10.7600/jpfsm.3.65 · Cited by 20
Circadian Dysrhythmias, Physiological Aberrations, and the Link to Skin Cancer
Gutiérrez, D., & Arbesman, J. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17050621 · Cited by 21
“Though it is known that core circadian clock proteins have functions outside of the central circadian pathways [26,27], the degree to which these proteins do is poorly understood and prevents concrete establishment of a cause–effect relationship between gene mutation and the resulting phenotype.”
BackgroundNon-obesogenic doses of fatty acids modulate the functionality of the circadian clock in the liver
Tal, Y., Chapnik, N., & Froy, O. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03023-6 · Cited by 21
Zhen, Y., Xi, Z., Hu, L., Chen, Y., Ge, L., Wei, W., Loor, J. J., Yang, Q., & Wang, M. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/7896371 · Cited by 21
“Several previous studies also showed that Per2 interacts with key nuclear receptors ( Ppar α , Ppar γ , and Rev-erb α ) [49] and plays an important role in the liver transcriptional response to feeding and acute fasting [50].”
Circadian rhythms and sleep—the metabolic connection
Albrecht, U. (2011) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-011-0986-6 · Cited by 19
“Regulation of neurotransmitter expression directly via clock components binding to E-boxes in promoters of the corresponding genes [35] as well as indirect regulation via nuclear receptors modulated by clock components such as PER2 [63] may shed new light on the interaction between circadian rhythms and sleep.”
BackgroundPERsuading nuclear receptors to dance the circadian rhythm
Ripperger, J. A., Schmutz, I., & Albrecht, U. (2010) · Cell Cycle · doi:10.4161/cc.9.13.12075 · Cited by 19
A ticking clock links metabolic pathways and organ systems function in health and disease
Vinciguerra, M., Tevy, M. F., & Mazzoccoli, G. (2013) · Clinical and Experimental Medicine · doi:10.1007/s10238-013-0235-8 · Cited by 20
“The core clock genes drive expression of nuclear receptors for several molecules, such as fatty acids, cholesterol, oxysterols, androgens, estrogens, glucocorticoids [10], and the circadian protein PER2 is able to bind rhythmically at the promoters of nuclear receptors target genes, co-regulating their transcription a…”
BackgroundTao, H., Li, X., Qiu, J., Cui, W., Sima, Y., & Xu, S. (2017) · Scientific Reports · doi:10.1038/srep46258 · Cited by 19
Santos, D. M., Buonfiglio, D. D. C., Garcia, R. A. P., Ramos-Lobo, A. M., Souza, D. N., Carpinelli, Â. R., Carvalho, C. R. D. O., Sertié, R. A. L., Andreotti, S., Lima, F. B., et al. (2018) · Nature and Science of Sleep · doi:10.2147/nss.s158602 · Cited by 17
“73 However Per2 may be acting as a transcription factor independent of the clock machinery in ZT21.”
Poliandri, A., Gamsby, J. J., Christian, M., Spinella, M. J., Loros, J., Dunlap, J., & Parker, M. G. (2011) · Journal of Biological Rhythms · doi:10.1177/0748730411401579 · Cited by 18
“In addition, these nuclear receptors are thought to be links between circadian rhythms and metabolism (Duguay and Cermakian, 2009; Schmutz et al., 2010).”
BackgroundResetting the Aging Clock: Implications for Managing Age-Related Diseases
Nobrega, A. K. D., Luz, K. V., & Lyons, L. C. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-42667-5_9 · Cited by 20
Pelham, J. F., Mosier, A. E., Altshuler, S. C., Rhodes, M. L., Kirchhoff, C. L., Fall, W. B., Mann, C., Baik, L. S., Chiu, J. C., & Hurley, J. (2021) · Cell Reports · doi:10.1016/j.celrep.2023.112376 · Cited by 19
More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα
Mansingh, S., Maier, G., Delezie, J., Westermark, P. O., Ritz, D., Duchemin, W., Santos, G., Karrer‐Cardel, B., Steurer, S. A., Albrecht, U., et al. (2024) · The Journal of Physiology · doi:10.1113/jp285585 · Cited by 18
“This is in line with previous studies that observed reduced fasting glycaemia and impaired gluconeogenesis in Per2 -mutant mice (Schmutz et al., 2010; Zani et al., 2013; Zhao et al., 2012).”
The contribution of circadian clock to the biological processes
Luo, B., Song, J., Zhang, J., Han, J., Zhou, X., & Chen, L. (2024) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2024.1387576 · Cited by 17
“The PER protein binds to nuclear receptors, such as REV-ERB α and PPAR α , regulating life activities, including growth and development, through nuclear receptor function (Grimaldi et al., 2010; Schmutz et al., 2010).”
BackgroundMosig, R., Castaneda, A. N., Deslauriers, J. C., Frazier, L. P., He, K. L., Maghzian, N., Pokharel, A., Schrier, C. T., Zhu, L., Koike, N., et al. (2021) · Genes & Development · doi:10.1101/gad.343541.120 · Cited by 18
“REV-ERB proteins, in turn, repress the expression of Bmal1, Clock, Npas2, Cry1 and Nfil3.”
BackgroundInfluentialYe, Y., Liu, C., Wu, R., Kang, D., Gao, H., Lv, H., Feng, Z., Shi, Y., Liu, Z., & Chen, L. (2024) · Mucosal Immunology · doi:10.1016/j.mucimm.2024.07.010 · Cited by 16
Genetic Interaction of Per1 and Dec1/2 in the Regulation of Circadian Locomotor Activity
Bode, B., Shahmoradi, A., Rossner, M. J., & Oster, H. (2011) · Journal of Biological Rhythms · doi:10.1177/0748730411419782 · Cited by 15
“A possible explanation for this effect would be that the altered phase relationship between the positive Bmal1 regulator Per2 (Schmutz et al., 2009; Shearman et al., 2000) and the transcriptional repressor Rev-Erba (Preitner et al.”
BackgroundPerreau‐Lenz, S., Hoelters, L.-S., Leixner, S., Sanchis‐Segura, C., Hansson, A. C., Bilbao, A., & Spanagel, R. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4574-0 · Cited by 17
Carbon monoxide-mediated humoral pathway for the transmission of light signal to the hypothalamus.
Gilun, P., Stefanczyk-Krzymowska, S., Romerowicz‐Misielak, M., Tabęcka-Łonczyńska, A., Przekop, F., & Koziorowski, M. (2013) · PubMed · Cited by 16
Impacts of high-sucrose diet on circadian rhythms in the small intestine of rats
Sun, S., Hanzawa, F., Umeki, M., Matsuyama, Y., Nishimura, N., Ikeda, S., Mochizuki, S., & Oda, H. (2019) · Chronobiology International · doi:10.1080/07420528.2019.1592185 · Cited by 16
“In addition, G6PC and FBP1 also have cAMP response elements similar to GLUT5 (El-Maghrabi et al. 1991; Schmoll et al. 1996), indicating potential regulation by circadian inhibitory transcription factors, such as PERs and CRYs, as mentioned earlier.”
BackgroundInfluentialShon, J., Han, Y., & Park, Y. J. (2022) · Nutrients · doi:10.3390/nu14030478 · Cited by 15
“Given that PER2 also interacts with nuclear receptors including PPARα and can regulate the expression of nuclear receptor target genes involved in lipid metabolism, PER2 polymorphisms could contribute to metabolic disorder vulnerability [68].”
BackgroundPartonen, T. (2012) · Frontiers in Neurology · doi:10.3389/fneur.2012.00157 · Cited by 14
“…genes that bear a signal of time in a correct phase throughout the tissues (Kornmann et al., 2007; Hughes et al., 2012), and the cryptochrome-independent influence of the PER2 protein on transcription of the ARNTL (BMAL1) gene (Schmutz et al., 2010; Ye et al., 2011) are not yet understood in depth.”
Period 2: A Regulator of Multiple Tissue-Specific Circadian Functions
Ruggiero, G., Livne, Z. B.-M., Wexler, Y., Geyer, N., Vallone, D., Gothilf, Y., & Foulkes, N. S. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.718387 · Cited by 15
“In particular, REV-ERBα and PPARα interact with the PER2 protein in the liver to regulate the transcription of their target genes (Schmutz et al., 2010).”
BackgroundRole of biological rhythms in the performance of physical activity
Sato, T., Ida, T., & Kojima, M. (2017) · The Journal of Physical Fitness and Sports Medicine · doi:10.7600/jpfsm.6.125 · Cited by 14
Diurnal expression of ABC and SLC transporters in jejunum is modulated by adrenalectomy
Vagnerová, K., Ergang, P., Soták, M., Balounová, K., Kvapilová, P., Vodička, M., & Pácha, J. (2019) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cbpc.2019.108607 · Cited by 14
Mosier, A. E., & Hurley, J. (2021) · Journal of Biological Rhythms · doi:10.1177/07487304211014622 · Cited by 10
Rheumatoid arthritis and the biological clock
Cata, A. D., D’Agruma, L., Tarquini, R., & Mazzoccoli, G. (2014) · Expert Review of Clinical Immunology · doi:10.1586/1744666x.2014.899904 · Cited by 13
“The results of the animal experiments showing increased cytokine production of synovial macrophages in response to melatonin [93] were in line with recent data reporting augmented nocturnal plasma melatonin levels in RA patients [94].”
ResultLi, S. K.-L., Banerjee, J., Jang, C., Sehgal, A., Stone, R. A., & Civan, M. M. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-15834 · Cited by 13
“In addition, the temperature cycling can synchronize the rhythms of the body’s cells through peripheral clocks expressed in most cells and tissues.(20,21,24) Changes in temperature and peripheral circadian rhythm are likely linked through heat shock transcription factor 1 (HSF1), which also functions as a circadian tr…”
BackgroundThe circadian clock in enamel development
Wu, K., Li, X., Bai, Y., Heng, B. C., Zhang, X., & Deng, X. (2024) · International Journal of Oral Science · doi:10.1038/s41368-024-00317-9 · Cited by 12
“Abnormal circadian rhythms have been reported to disrupt the formation of mandibular fi rst molar germs in mice, characterized by reduced protein expression levels of BMAL1 and PER2, as well as decreased immunohistochemical staining of BMAL1 and PER2 in ameloblasts.”
BackgroundWang, J., Luo, Y., Wang, K., Wang, Y., Zhang, X., Teng, H., & Sun, Z. S. (2014) · Chronobiology International · doi:10.3109/07420528.2014.982284 · Cited by 12
“…revealed that Per2 could directly interact with nuclear receptors, including peroxisome proliferator-activated receptor-alpha (PPAR-a) and REV-ERBa (Schmutz et al., 2010); the former exhibits anti-inflammatory and immunomodulatory activity (Kidani & Bensinger, 2012), and the later could modulate…”
BackgroundInfluentialOyama, Y., Shuff, S. R., Burns, N., Vohwinkel, C. U., & Eckle, T. D. L. G. (2022) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00301.2021 · Cited by 12
The PXDLS linear motif regulates circadian rhythmicity through protein–protein interactions
Shalev, M., Aviram, R., Adamovich, Y., Kraut‐Cohen, J., Shamia, T., Ben‐Dor, S., Golik, M., & Asher, G. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku873 · Cited by 11
“participates in PER2 interactions with various nuclear receptors and plays a role in circadian gene expression (22).”
Circadian Angiopoietin-Like-4 as a Novel Therapy in Cardiovascular Disease
Shuff, S. R., Oyama, Y., Walker, L. A., & Eckle, T. D. L. G. (2021) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2021.04.007 · Cited by 11
The Circadian Clock and Obesity
Sebti, Y., Hebras, A., Pourcet, B., Staels, B., & Duez, H. (2022) · Handbook of experimental pharmacology · doi:10.1007/164_2021_579 · Cited by 13
Taira, A., Arita, E., Matsumoto, E., Oohira, A., Iwase, K., Hiwasa, T., Yokote, K., Shibata, S., & Takiguchi, M. (2019) · Chronobiology International · doi:10.1080/07420528.2019.1570246 · Cited by 11
“…clock component (Bunger et al. 2000), only moderately affected hepatic Pck1 expression rhythms, while whole-body disruption of clock genes had varying results (Doi et al. 2010; Kennaway et al. 2007, 2013; LeMartelot et al. 2009; Marcheva et al. 2010; Schmutz et al. 2010; Zani et al. 2013).”
BackgroundInfluentialDeletion of exons 3 and 4 in the mouse Nr1d1 gene worsens high-fat diet-induced hepatic steatosis
Na, H., Lee, H., Lee, M.-H., Lim, H. J., Kim, H., Jeon, Y., Kang, H.-L., & Lee, M. (2016) · Life Sciences · doi:10.1016/j.lfs.2016.10.003 · Cited by 10
Metaboloepigenetics: The Emerging Network in Stem Cell Homeostasis Regulation
Avitabile, D., Magenta, A., Lauri, A., Gambini, E., Spaltro, G., & Vinci, M. C. (2016) · Current Stem Cell Research & Therapy · doi:10.2174/1574888x11666151203223839 · Cited by 10
Murray, A., Tharmalingam, S., Nguyen, P., & Tai, T. C. (2021) · Scientific Reports · doi:10.1038/s41598-021-99598-x · Cited by 10
Introduction to the Clock System
Cox, K. H., & Takahashi, J. S. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-81147-1_1 · Cited by 11
Ripperger, J. A., Chavan, R., Albrecht, U., & Brenna, A. (2022) · Clocks & Sleep · doi:10.3390/clockssleep4010017 · Cited by 11
“The antibodies against all the clock factors were described [52] (final dilution 1:1000).”
BackgroundCircadian Clock Proteins in Mood Regulation
Partonen, T. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2014.00195 · Cited by 9
“In addition, the direct interaction of PER2 with NR1D1 (55) may feedback to this vicious circle that was initiated by the overactive brown adipose tissue.”
BackgroundFagiani, F., Baronchelli, E., Pittaluga, A., Pedrini, E., Scacchi, C., Govoni, S. M., & Lanni, C. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.937174 · Cited by 10
PERspectives on circadian cell biology
Mihut, A., O'Neill, J. S., Partch, C. L., & Crosby, P. (2025) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2023.0483 · Cited by 15
Hypothesis driven single cell dual oscillator mathematical model of circadian rhythms
Sisobhan, S., & Sriram, K. (2017) · PLoS ONE · doi:10.1371/journal.pone.0177197 · Cited by 8
Expression of Clock Genes in Human Subcutaneous and Visceral Adipose Tissues
Zanquetta, M. M., Corrêa‐Giannella, M. L., Giannella‐Neto, D., Alonso, P. A., Guimaraes, L. M. M. V., Meyer, A., & Villares, S. M. (2012) · Chronobiology International · doi:10.3109/07420528.2012.657319 · Cited by 8
“For instance, PER2 interacts with PPARα and REV-ERBα, participating in the regulation of lipogenesis and gluconeogenesis (Schmutz et al., 2010).”
BackgroundBass, J. T. (2011) · Nature · doi:10.1038/480466a · Cited by 10
Measuring Food Anticipation in Mice
Martini, T., Ripperger, J. A., & Albrecht, U. (2018) · Clocks & Sleep · doi:10.3390/clockssleep1010007 · Cited by 7
“These in turn either positively or negatively regulate Bmal1 and Clock/Npas2, providing a feedback loop (Figure 1) [2,3,8,10].”
BackgroundCommentary: The Year in Circadian Rhythms
Sassone‐Corsi, P. (2010) · Molecular Endocrinology · doi:10.1210/me.2010-0359 · Cited by 8
Clock genes in pancreatic disease progression: from circadian regulation to dysfunction
Zheng, T., Wang, K., Shi, Q., Zhang, L., Yan, Q., Jiang, W., Chen, C., Zhao, K., Feng, J., & Wang, W. (2025) · Annals of Medicine · doi:10.1080/07853890.2025.2528449 · Cited by 9
“Recent human studies have highlighted the critical role of clock genes in regulating normal pancreatic islet function, particularly in insulin secretion [42].”
Huang, Y., Gao, X., Yang, E., Yue, K., Cao, Y., Zhao, B., Zhang, H., Dai, S., Zhang, L., Luo, P., et al. (2022) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17244 · Cited by 6
Velásquez-Jiménez, D., Luzardo‐Ocampo, I., Gaytán‐Martínez, M., & Campos-Vega, R. (2023) · Food Bioscience · doi:10.1016/j.fbio.2023.103199 · Cited by 7
Thyroid Hormone-Regulated Expression of Period2 Promotes Liver Urate Production
Chen, X., Wu, M., Liang, N., Lu, J., Qu, S., & Chen, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.636802 · Cited by 7
Lalpekhlui, R., Renthlei, Z., & Trivedi, A. K. (2022) · Chronobiology International · doi:10.1080/07420528.2022.2062374 · Cited by 7
“Besides transcriptional regulation, PPARα could modulate PER2 activity by direct physical interactions (Schmutz et al. 2010).”
BackgroundHorloges circadiennes et métabolisme : intégration des signaux métaboliques et environnementaux
Duez, H., Sebti, Y., & Staels, B. (2013) · médecine/sciences · doi:10.1051/medsci/2013298017 · Cited by 10
“Lamia KA, Papp SJ, Yu RT, et al. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor.”
InfluentialNature’s Timepiece—Molecular Coordination of Metabolism and Its Impact on Aging
Bednářová, A., Kodrík, D., & Krishnan, N. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14023026 · Cited by 7
“information to metabolic genes by directly interacting with and acting as a co-regulator of nuclear receptor-mediated transcription [69].”
BackgroundSynchronization of the mammalian central and peripheral circadian clocks
Qin, X., & Guo, J. (2017) · Chinese Science Bulletin (Chinese Version) · doi:10.1360/n972017-00542 · Cited by 6
Pelham, J. F., Mosier, A. E., Altshuler, S. C., Kirchhoff, C. L., Fall, W. B., Baik, L. S., Chiu, J. C., & Hurley, J. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3982676 · Cited by 7
Epigenetic events influencing the biological clock: Panacea for neurodegeneration
Laxmi, I. P. L., & Tamizhselvi, R. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e38836 · Cited by 8
“A study by Schmutz and team found that PER2 combined with PPAR caused alteration in its activity at target genes involved in metabolism like glucose 6-phosphatase explicitly with the activities of Peroxisome proliferator-activated receptor gamma to control lipid metabolism [114, 115].”
BackgroundSchindler, K. A., Torices, S., Schurhoff, N. A., Gallo, D. I., & Toborek, M. J. (2025) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2025.115645 · Cited by 8
Bhaskar, R., Narayanan, K. B., Singh, D. K. K., & Han, S. S. (2025) · Current Alzheimer Research · doi:10.2174/0115672050381989250626071304 · Cited by 7
Epoxiconazole alters the histology and transcriptome of mouse liver in a transgenerational pattern
Corre, L. L., Brulport, A., Vaiman, D., & Chagnon, M. (2022) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2022.109952 · Cited by 6
The Role of FBXW Subfamily of F-box Proteins in Tumorigenesis
Lau, A. W., Liu, Y., Tron, A. E., Inuzuka, H., & Wei, W. (2014) · Springer eBooks · doi:10.1007/978-3-319-05026-3_2 · Cited by 6
Circadian systems biology in Metazoa
Lin, L., Huang, H., Juan, H., & for the 2014 Taida Cancer Systems Biology Study Group (2015) · Briefings in Bioinformatics · doi:10.1093/bib/bbv006 · Cited by 6
Circadian Rhythm and Nuclear Receptors
Ray, D. W. (2022) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-11836-4_8 · Cited by 7
Direct regulation of Per2 by Roraa: insights into circadian and metabolic interplay in zebrafish
Yang, M., Liu, Y., Zhong, Z., Ou, Y., Wang, M., Zhong, Y., & Liu, C. (2025) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-025-05696-8 · Cited by 6
“In mammals, the regulation of this loop is achieved by REV-ERBα [28].”
Rouibate, A. D., Benhafri, N., Ouali‐Hassenaoui, S., & Dekar-Madoui, A. (2020) · Folia Histochemica et Cytobiologica · doi:10.5603/fhc.a2020.0021 · Cited by 5
Dynamics of the circadian clock protein PERIOD2 in living cells
Öllinger, R., Korge, S., Korte, T., Koller, B., Herrmann, A., & Kramer, A. (2014) · Development · doi:10.1242/dev.118000 · Cited by 5
“, 1998), as well as the nuclear receptors REV-ERBa (also known as NR1D1) and PPARa (Schmutz et al., 2010).”
BackgroundCore Circadian Protein BMAL1: Implication for Nervous System Functioning and Its Diseases
Smirnova, K. V., Smirnova, L. P., & Amstislavskaya, T. G. (2025) · Brain Sciences · doi:10.3390/brainsci15121321 · Cited by 4
“PER2 is also able to interact with the nuclear receptors REV-ERB α and PPAR α (peroxisome proliferator-activated receptor α ) on Bmal1 promoters, which act as transcriptional corepressors and coactivators, respectively [17].”
The causal association between thyroid disease and gout: A Mendelian randomization study
Song, S., Jia, C., Li, C., & Ma, Y. (2023) · Medicine · doi:10.1097/md.0000000000035817 · Cited by 4
“[34] Studies have shown that T3 can affect the levels of enzymes involved in nucleotide metabolism in the liver and promote urate production by inducing Per2 expression, revealing a potential mechanism between thyroid disease and gout.”
BackgroundBerthier, A., Gheeraert, C., Vinod, M., Johanns, M., Guille, L., Haas, J. T., Dubois‐Chevalier, J., Eeckhoute, J., Staels, B., & Lefèbvre, P. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2025.02.004 · Cited by 4
A wrinkle in timers: evolutionary rewiring of conserved biological timekeepers
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“This suggests parallels between LIN-42/NHR crosstalk in C. elegans and PER2 regulation within the mammalian secondary loop [35,36].”
Circadian Clocks, Sleep, and Metabolism
Nowak, N., Rawleigh, A., & Brown, S. A. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-81147-1_2 · Cited by 4
The Role of the Circadian System in Homeostasis
Venkataraman, A., Ballance, H. I., & Hogenesch, J. B. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-385944-0.00021-6 · Cited by 4
Thraya, M., Patel, A., Stewart, K., Abou-Akl, H., Roberts, D., Heath, D. D., Pitcher, T. E., Carmona‐Alcocer, V., & Karpowicz, P. A. (2025) · Scientific Reports · doi:10.1038/s41598-025-01069-0 · Cited by 4
Circadian Rhythms and Metabolism
Challet, É., & Kalsbeek, A. (2017) · Frontiers research topics · doi:10.3389/978-2-88945-282-8 · Cited by 3
Boudjelal, M. (2013) · Journal of Carcinogenesis & Mutagenesis · doi:10.4172/2157-2518.s14-005 · Cited by 2
“The best characterized loop to date, is the secondary loop orchestrated by REV-ERBα and RORα nuclear receptors [19].”
BackgroundIntroduction to Mammalian Circadian Clock System
Zhao, M., Lu, D., Chen, M., & Wu, B. (2020) · Springer eBooks · doi:10.1007/978-981-15-8807-5_1 · Cited by 4
Zhang, T., Liu, M., Yang, Y., Wang, K., Zhao, H., & Pan, C. (2021) · Animal Biotechnology · doi:10.1080/10495398.2021.1998091 · Cited by 3
“found that PER regulates the expression of nuclear receptor target genes, such as Hnf1a and Glucose-6-phosphatase, by rhythmically binding to the promoter of nuclear receptor target genes.(33)”
BackgroundMa, H., Liu, S., Wei, P., Fei, F., Ren, J., Dai, M., Ma, Z., & Liu, Y. (2023) · Frontiers in Marine Science · doi:10.3389/fmars.2022.1005352 · Cited by 3
“In mammals, the genes located in the main feedback loop include Clock and its homologous genes Npas2, Arntl1, Per1, Per2, Cry1, Cry2 (Schmutz et al., 2010).”
BackgroundPrecision medicine in endocrinology: Unraveling metabolic health through time-restricted eating
Chavanne, A., & Jacobi, D. (2023) · Annales d Endocrinologie · doi:10.1016/j.ando.2023.12.001 · Cited by 3
Quantification of interactions among circadian clock proteins via surface plasmon resonance
Kepsutlu, B., Kizilel, R., & Kızılel, S. (2014) · Journal of Molecular Recognition · doi:10.1002/jmr.2367 · Cited by 3
“Previous biochemical studies suggest that CRY2 binds to EBOX (Ye et al., 2011); however, biochemical studies conflict about the binding of PER2 and PER2 : CRY2 with BMAL1 : CLOCK : EBOX complex (Chen et al., 2009; Schmutz et al., 2010; Ye et al., 2011; Huang et al., 2012).”
BackgroundLrrc34 Is Highly Expressed in SSCs and Is Necessary for SSC Expansion In Vitro
Ou, J., Li, Y., Wang, Z., Cheng, J. H., Li, K., Lu, Y., Zou, D., Li, P., Li, M., Shiying, M., et al. (2020) · Chinese Medical Sciences Journal · doi:10.24920/003680 · Cited by 3
“NCOR1 and CREB1 in the second module are all related to transcription regulation, [21-27] and TRIM69, FBXO22, SMURF2 and FBXL19 in the third module are relevant to the ubiquitination process via the E3 ubiquitin ligase, which includes substrate recognition.”
BackgroundRebuelto, M. (2012) · ChronoPhysiology and Therapy · doi:10.2147/cpt.s21855 · Cited by 3
“69–72 In fact, experiments performed with human and monkey kidney cells suggest that PPARs and clock genes cross regulate each other at the transcription level.”
A circadian-like gene network regulates heterochronic miRNA transcription in C. elegansPreprint
Kinney, B. A., Sahu, S., Stec, N., Hills-Muckey, K., Adams, D. W., Wang, J., Jaremko, M. J., Joshua‐Tor, L., Keil, W. W., & Hammell, C. M. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.26.509508 · Cited by 3
Hassan, S. A., Stumpe, M., Hui, K. Y., Giraud, M.-N., Albrecht, U., & Ripperger, J. A. (2025) · Scientific Reports · doi:10.1038/s41598-025-34303-w · Cited by 2
“Antibodies for BMAL1 and PER2 have been described 41 , while we used anti-HSP90a/b (sc-13119, Santa Cruz, Dallas, TX, USA) and anti-AGT (79299 S, Cell Signaling Technology, Danvers, MA, USA) and the appropriate secondary antibodies coupled to horseradish peroxidase.”
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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