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1
Xiao, Yangbo, Ye Yuan, Mariana Jimenez, Neeraj Soni, and Swathi Yadlapalli. "Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms." Proceedings of the National Academy of Sciences 118, no. 28 (July 7, 2021): e2019756118. http://dx.doi.org/10.1073/pnas.2019756118.
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Circadian clocks regulate ∼24-h oscillations in gene expression, behavior, and physiology. While the genetic and molecular mechanisms of circadian rhythms are well characterized, what remains poorly understood are the intracellular dynamics of circadian clock components and how they affect circadian rhythms. Here, we elucidate how spatiotemporal organization and dynamics of core clock proteins and genes affect circadian rhythms in Drosophila clock neurons. Using high-resolution imaging and DNA-fluorescence in situ hybridization techniques, we demonstrate that Drosophila clock proteins (PERIOD and CLOCK) are organized into a few discrete foci at the nuclear envelope during the circadian repression phase and play an important role in the subnuclear localization of core clock genes to control circadian rhythms. Specifically, we show that core clock genes, period and timeless, are positioned close to the nuclear periphery by the PERIOD protein specifically during the repression phase, suggesting that subnuclear localization of core clock genes might play a key role in their rhythmic gene expression. Finally, we show that loss of Lamin B receptor, a nuclear envelope protein, leads to disruption of PER foci and per gene peripheral localization and results in circadian rhythm defects. These results demonstrate that clock proteins play a hitherto unexpected role in the subnuclear reorganization of core clock genes to control circadian rhythms, revealing how clocks function at the subcellular level. Our results further suggest that clock protein foci might regulate dynamic clustering and spatial reorganization of clock-regulated genes over the repression phase to control circadian rhythms in behavior and physiology.
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Lu, Renbin, Yufan Dong, and Jia-Da Li. "Necdin regulates BMAL1 stability and circadian clock through SGT1-HSP90 chaperone machinery." Nucleic Acids Research 48, no. 14 (July 15, 2020): 7944–57. http://dx.doi.org/10.1093/nar/gkaa601.
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Abstract Circadian clocks are endogenous oscillators that control ∼24-hour physiology and behaviors in virtually all organisms. The circadian oscillator comprises interconnected transcriptional and translational feedback loops, but also requires finely coordinated protein homeostasis including protein degradation and maturation. However, the mechanisms underlying the mammalian clock protein maturation is largely unknown. In this study, we demonstrate that necdin, one of the Prader-Willi syndrome (PWS)-causative genes, is highly expressed in the suprachiasmatic nuclei (SCN), the pacemaker of circadian clocks in mammals. Mice deficient in necdin show abnormal behaviors during an 8-hour advance jet-lag paradigm and disrupted clock gene expression in the liver. By using yeast two hybrid screening, we identified BMAL1, the core component of the circadian clock, and co-chaperone SGT1 as two necdin-interactive proteins. BMAL1 and SGT1 associated with the N-terminal and C-terminal fragments of necdin, respectively. Mechanistically, necdin enables SGT1-HSP90 chaperone machinery to stabilize BMAL1. Depletion of necdin or SGT1/HSP90 leads to degradation of BMAL1 through the ubiquitin–proteasome system, resulting in alterations in both clock gene expression and circadian rhythms. Taken together, our data identify the PWS-associated protein necdin as a novel regulator of the circadian clock, and further emphasize the critical roles of chaperone machinery in circadian clock regulation.
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Fu, Minnie, and Xiaoyong Yang. "The sweet tooth of the circadian clock." Biochemical Society Transactions 45, no. 4 (July 3, 2017): 871–84. http://dx.doi.org/10.1042/bst20160183.
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The endogenous circadian clock is a key regulator of daily metabolic processes. On the other hand, circadian clocks in a broad range of tissues can be tuned by extrinsic and intrinsic metabolic cues. The bidirectional interaction between circadian clocks and metabolism involves both transcriptional and post-translational mechanisms. Nuclear receptors exemplify the transcriptional programs that couple molecular clocks to metabolism. The post-translational modifications of the core clock machinery are known to play a key role in metabolic entrainment of circadian clocks. O-linked N-acetylglucosamine modification (O-GlcNAcylation) of intracellular proteins is a key mediator of metabolic response to nutrient availability. This review highlights our current understanding of the role of protein O-GlcNAcylation in mediating metabolic input and output of the circadian clock.
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Mosier, Alexander E., and Jennifer M. Hurley. "Circadian Interactomics: How Research Into Protein-Protein Interactions Beyond the Core Clock Has Influenced the Model of Circadian Timekeeping." Journal of Biological Rhythms 36, no. 4 (May 31, 2021): 315–28. http://dx.doi.org/10.1177/07487304211014622.
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The circadian clock is the broadly conserved, protein-based, timekeeping mechanism that synchronizes biology to the Earth’s 24-h light-dark cycle. Studies of the mechanisms of circadian timekeeping have placed great focus on the role that individual protein-protein interactions play in the creation of the timekeeping loop. However, research has shown that clock proteins most commonly act as part of large macromolecular protein complexes to facilitate circadian control over physiology. The formation of these complexes has led to the large-scale study of the proteins that comprise these complexes, termed here “circadian interactomics.” Circadian interactomic studies of the macromolecular protein complexes that comprise the circadian clock have uncovered many basic principles of circadian timekeeping as well as mechanisms of circadian control over cellular physiology. In this review, we examine the wealth of knowledge accumulated using circadian interactomics approaches to investigate the macromolecular complexes of the core circadian clock, including insights into the core mechanisms that impart circadian timing and the clock’s regulation of many physiological processes. We examine data acquired from the investigation of the macromolecular complexes centered on both the activating and repressing arm of the circadian clock and from many circadian model organisms.
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Fuchikawa, T., K. Beer, C. Linke-Winnebeck, R. Ben-David, A. Kotowoy, V. W. K. Tsang, G. R. Warman, E. C. Winnebeck, C. Helfrich-Förster, and G. Bloch. "Neuronal circadian clock protein oscillations are similar in behaviourally rhythmic forager honeybees and in arrhythmic nurses." Open Biology 7, no. 6 (June 2017): 170047. http://dx.doi.org/10.1098/rsob.170047.
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Internal clocks driving rhythms of about a day (circadian) are ubiquitous in animals, allowing them to anticipate environmental changes. Genetic or environmental disturbances to circadian clocks or the rhythms they produce are commonly associated with illness, compromised performance or reduced survival. Nevertheless, some animals including Arctic mammals, open sea fish and social insects such as honeybees are active around-the-clock with no apparent ill effects. The mechanisms allowing this remarkable natural plasticity are unknown. We generated and validated a new and specific antibody against the clock protein PERIOD of the honeybee Apis mellifera (amPER) and used it to characterize the circadian network in the honeybee brain. We found many similarities to Drosophila melanogaster and other insects, suggesting common anatomical organization principles in the insect clock that have not been appreciated before. Time course analyses revealed strong daily oscillations in amPER levels in foragers, which show circadian rhythms, and also in nurses that do not, although the latter have attenuated oscillations in brain mRNA clock gene levels. The oscillations in nurses show that activity can be uncoupled from the circadian network and support the hypothesis that a ticking circadian clock is essential even in around-the-clock active animals in a constant physical environment.
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Zhang, Yang, Chunyan Duan, Jing Yang, Suping Chen, Qing Liu, Liang Zhou, Zhengyun Huang, Ying Xu, and Guoqiang Xu. "Deubiquitinating enzyme USP9X regulates cellular clock function by modulating the ubiquitination and degradation of a core circadian protein BMAL1." Biochemical Journal 475, no. 8 (April 30, 2018): 1507–22. http://dx.doi.org/10.1042/bcj20180005.
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Living organisms on the earth maintain a roughly 24 h circadian rhythm, which is regulated by circadian clock genes and their protein products. Post-translational modifications of core clock proteins could affect the circadian behavior. Although ubiquitination of core clock proteins was studied extensively, the reverse process, deubiquitination, has only begun to unfold and the role of this regulation on circadian function is not completely understood. Here, we use affinity purification and mass spectrometry analysis to identify probable ubiquitin carboxyl-terminal hydrolase FAF-X (USP9X) as an interacting protein of the core clock protein aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL or BMAL1). Through biochemical experiments, we discover that USP9X reduces BMAL1 ubiquitination, enhances its stability, and increases its protein level, leading to the elevated transcriptional activity. Bioluminescence measurement reveals that USP9X knockdown decreases the amplitude of the cellular circadian rhythm but the period and phase are not affected. Our experiments find a new regulator for circadian clock at the post-translational level and demonstrate a different regulatory function for the circadian clock through the deubiquitination and the up-regulation of the core clock protein BMAL1 in the positive limb of the transcription–translation feedback loop.
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Durgan, David J., Margaret A. Hotze, Tara M. Tomlin, Oluwaseun Egbejimi, Christophe Graveleau, E. Dale Abel, Chad A. Shaw, Molly S. Bray, Paul E. Hardin, and Martin E. Young. "The intrinsic circadian clock within the cardiomyocyte." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 4 (October 2005): H1530—H1541. http://dx.doi.org/10.1152/ajpheart.00406.2005.
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Circadian clocks are intracellular molecular mechanisms that allow the cell to anticipate the time of day. We have previously reported that the intact rat heart expresses the major components of the circadian clock, of which its rhythmic expression in vivo is consistent with the operation of a fully functional clock mechanism. The present study exposes oscillations of circadian clock genes [brain and arylhydrocarbon receptor nuclear translocator-like protein 1 ( bmal1), reverse strand of the c-erbaα gene ( rev-erbaα), period 2 ( per2), albumin D-element binding protein ( dbp)] for isolated adult rat cardiomyocytes in culture. Acute (2 h) and/or chronic (continuous) treatment of cardiomyocytes with FCS (50% and 2.5%, respectively) results in rhythmic expression of circadian clock genes with periodicities of 20–24 h. In contrast, cardiomyocytes cultured in the absence of serum exhibit dramatically dampened oscillations in bmal1 and dbp only. Zeitgebers (timekeepers) are factors that influence the timing of the circadian clock. Glucose, which has been previously shown to reactivate circadian clock gene oscillations in fibroblasts, has no effect on the expression of circadian clock genes in adult rat cardiomyocytes, either in the absence or presence of serum. Exposure of adult rat cardiomyocytes to the sympathetic neurotransmitter norephinephrine (10 μM) for 2 h reinitiates rhythmic expression of circadian clock genes in a serum-independent manner. Oscillations in circadian clock genes were associated with 24-h oscillations in the metabolic genes pyruvate dehydrogenase kinase 4 ( pdk4) and uncoupling protein 3 ( ucp3). In conclusion, these data suggest that the circadian clock operates within the myocytes of the heart and that this molecular mechanism persists under standard cell culture conditions (i.e., 2.5% serum). Furthermore, our data suggest that norepinephrine, unlike glucose, influences the timing of the circadian clock within the heart and that the circadian clock may be a novel mechanism regulating myocardial metabolism.
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Graf, Alexander, Diana Coman, R. Glen Uhrig, Sean Walsh, Anna Flis, Mark Stitt, and Wilhelm Gruissem. "Parallel analysis of Arabidopsis circadian clock mutants reveals different scales of transcriptome and proteome regulation." Open Biology 7, no. 3 (March 2017): 160333. http://dx.doi.org/10.1098/rsob.160333.
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The circadian clock regulates physiological processes central to growth and survival. To date, most plant circadian clock studies have relied on diurnal transcriptome changes to elucidate molecular connections between the circadian clock and observable phenotypes in wild-type plants. Here, we have integrated RNA-sequencing and protein mass spectrometry data to comparatively analyse the lhycca1 , prr7prr9 , gi and toc1 circadian clock mutant rosette at the end of day and end of night. Each mutant affects specific sets of genes and proteins, suggesting that the circadian clock regulation is modular. Furthermore, each circadian clock mutant maintains its own dynamically fluctuating transcriptome and proteome profile specific to subcellular compartments. Most of the measured protein levels do not correlate with changes in their corresponding transcripts. Transcripts and proteins that have coordinated changes in abundance are enriched for carbohydrate- and cold-responsive genes. Transcriptome changes in all four circadian clock mutants also affect genes encoding starch degradation enzymes, transcription factors and protein kinases. The comprehensive transcriptome and proteome datasets demonstrate that future system-driven research of the circadian clock requires multi-level experimental approaches. Our work also shows that further work is needed to elucidate the roles of post-translational modifications and protein degradation in the regulation of clock-related processes.
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Clark, Amelia M., and Brian J. Altman. "Circadian control of macrophages in the tumor microenvironment." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 165.06. http://dx.doi.org/10.4049/jimmunol.208.supp.165.06.
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Abstract Introduction All leukocytes tested to date have functional circadian clocks, and nearly every arm of the immune response is subject to circadian regulation. Circadian clocks instruct the time-of-day-dependent, rhythmic expression of genes in a tissue- and cell-specific manner. In macrophages (mΦs), the circadian clock regulates several factors that are critical to executing effective immune responses. Tumor-associated mΦs are major contributors to immune suppression in the tumor microenvironment (TME). Evidence suggests that metabolically stressful factors in the TME such as acidic pH and nutrient limitation promote mΦ-mediated immune suppression, and recent data point to dysregulation of the circadian clock downstream of metabolic stress. Methods We study the effect of TME-associated metabolic stress on the circadian clock of mΦs in vitro by culturing bone marrow-derived mΦs in conditions mimicking acidic pH and nutrient limitations that have been observed in the TME. To study the impact of mΦ-intrinsic circadian rhythms on tumorigenesis in vivo, we use mice genetically engineered to have a myeloid cell-specific disruption of the circadian clock via deletion of the key clock protein BMAL1. Results Oscillation of core clock proteins is altered in mΦs subjected to TME-associated metabolic stress. Additionally, we observe increased tumor growth in mice co-injected with mΦs whose circadian clocks were disrupted compared to mice co-injected with mΦs whose circadian clocks were functional. Conclusion Our data suggests that stressful conditions associated with the TME can alter the mΦ circadian clock, and that a functional circadian clock in mΦs can suppress tumor growth in a syngeneic murine tumor model of pancreatic cancer. This research has been supported by the following fellowships and grants: 2021-Current: Wilmot Predoctoral Cancer Research Fellowship, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 2020-2021: NIH T32 Training Grant in Cellular, Biochemical & Molecular Sciences, University of Rochester Medical Center, Rochester, NY
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Narumi, Ryohei, Yoshihiro Shimizu, Maki Ukai-Tadenuma, Koji L. Ode, Genki N. Kanda, Yuta Shinohara, Aya Sato, Katsuhiko Matsumoto, and Hiroki R. Ueda. "Mass spectrometry-based absolute quantification reveals rhythmic variation of mouse circadian clock proteins." Proceedings of the National Academy of Sciences 113, no. 24 (May 31, 2016): E3461—E3467. http://dx.doi.org/10.1073/pnas.1603799113.
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Absolute values of protein expression levels in cells are crucial information for understanding cellular biological systems. Precise quantification of proteins can be achieved by liquid chromatography (LC)–mass spectrometry (MS) analysis of enzymatic digests of proteins in the presence of isotope-labeled internal standards. Thus, development of a simple and easy way for the preparation of internal standards is advantageous for the analyses of multiple target proteins, which will allow systems-level studies. Here we describe a method, termed MS-based Quantification By isotope-labeled Cell-free products (MS-QBiC), which provides the simple and high-throughput preparation of internal standards by using a reconstituted cell-free protein synthesis system, and thereby facilitates both multiplexed and sensitive quantification of absolute amounts of target proteins. This method was applied to a systems-level dynamic analysis of mammalian circadian clock proteins, which consist of transcription factors and protein kinases that govern central and peripheral circadian clocks in mammals. Sixteen proteins from 20 selected circadian clock proteins were successfully quantified from mouse liver over a 24-h time series, and 14 proteins had circadian variations. Quantified values were applied to detect internal body time using a previously developed molecular timetable method. The analyses showed that single time-point data from wild-type mice can predict the endogenous state of the circadian clock, whereas data from clock mutant mice are not applicable because of the disappearance of circadian variation.
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Abdalla, Osama Hasan Mustafa Hasan, Brittany Mascarenhas, and Hai-Ying Mary Cheng. "Death of a Protein: The Role of E3 Ubiquitin Ligases in Circadian Rhythms of Mice and Flies." International Journal of Molecular Sciences 23, no. 18 (September 12, 2022): 10569. http://dx.doi.org/10.3390/ijms231810569.
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Circadian clocks evolved to enable organisms to anticipate and prepare for periodic environmental changes driven by the day–night cycle. This internal timekeeping mechanism is built on autoregulatory transcription–translation feedback loops that control the rhythmic expression of core clock genes and their protein products. The levels of clock proteins rise and ebb throughout a 24-h period through their rhythmic synthesis and destruction. In the ubiquitin–proteasome system, the process of polyubiquitination, or the covalent attachment of a ubiquitin chain, marks a protein for degradation by the 26S proteasome. The process is regulated by E3 ubiquitin ligases, which recognize specific substrates for ubiquitination. In this review, we summarize the roles that known E3 ubiquitin ligases play in the circadian clocks of two popular model organisms: mice and fruit flies. We also discuss emerging evidence that implicates the N-degron pathway, an alternative proteolytic system, in the regulation of circadian rhythms. We conclude the review with our perspectives on the potential for the proteolytic and non-proteolytic functions of E3 ubiquitin ligases within the circadian clock system.
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Leloup, Jean-Christophe. "Circadian clocks and phosphorylation: Insights from computational modeling." Open Life Sciences 4, no. 3 (September 1, 2009): 290–303. http://dx.doi.org/10.2478/s11535-009-0025-1.
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AbstractCircadian clocks are based on a molecular mechanism regulated at the transcriptional, translational and post-translational levels. Recent experimental data unravel a complex role of the phosphorylations in these clocks. In mammals, several kinases play differential roles in the regulation of circadian rhythmicity. A dysfunction in the phosphorylation of one clock protein could lead to sleep disorders such as the Familial Advanced Sleep Phase Disorder, FASPS. Moreover, several drugs are targeting kinases of the circadian clocks and can be used in cancer chronotherapy or to treat mood disorders. In Drosophila, recent experimental observations also revealed a complex role of the phosphorylations. Because of its high degree of homology with mammals, the Drosophila system is of particular interest. In the circadian clock of cyanobacteria, an atypical regulatory mechanism is based only on three clock proteins (KaiA, KaiB, KaiC) and ATP and is sufficient to produce robust temperature-compensated circadian oscillations of KaiC phosphorylation. This review will show how computational modeling has become a powerful and useful tool in investigating the regulatory mechanism of circadian clocks, but also how models can give rise to testable predictions or reveal unexpected results.
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Tian, Wenwen, Ruyi Wang, Cunpei Bo, Yingjun Yu, Yuanyuan Zhang, Gyeong-Im Shin, Woe-Yeon Kim, and Lei Wang. "SDC mediates DNA methylation-controlled clock pace by interacting with ZTL in Arabidopsis." Nucleic Acids Research 49, no. 7 (March 1, 2021): 3764–80. http://dx.doi.org/10.1093/nar/gkab128.
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Abstract Molecular bases of eukaryotic circadian clocks mainly rely on transcriptional-translational feedback loops (TTFLs), while epigenetic codes also play critical roles in fine-tuning circadian rhythms. However, unlike histone modification codes that play extensive and well-known roles in the regulation of circadian clocks, whether DNA methylation (5mC) can affect the circadian clock, and the associated underlying molecular mechanisms, remains largely unexplored in many organisms. Here we demonstrate that global genome DNA hypomethylation can significantly lengthen the circadian period of Arabidopsis. Transcriptomic and genetic evidence demonstrate that SUPPRESSOR OF drm1 drm2 cmt3 (SDC), encoding an F-box containing protein, is required for the DNA hypomethylation-tuned circadian clock. Moreover, SDC can physically interact with another F-box containing protein ZEITLUPE (ZTL) to diminish its accumulation. Genetic analysis further revealed that ZTL and its substrate TIMING OF CAB EXPRESSION 1 (TOC1) likely act downstream of DNA methyltransferases to control circadian rhythm. Together, our findings support the notion that DNA methylation is important to maintain proper circadian pace in Arabidopsis, and further established that SDC links DNA hypomethylation with a proteolytic cascade to assist in tuning the circadian clock.
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Jaeger, Cassie, Ali Q. Khazaal, Canxin Xu, Mingwei Sun, Stacey L. Krager, and Shelley A. Tischkau. "Aryl Hydrocarbon Receptor Deficiency Alters Circadian and Metabolic Rhythmicity." Journal of Biological Rhythms 32, no. 2 (March 27, 2017): 109–20. http://dx.doi.org/10.1177/0748730417696786.
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PAS domain–containing proteins can act as environmental sensors that capture external stimuli to allow coordination of organismal physiology with the outside world. These proteins permit diverse ligand binding and heterodimeric partnership, allowing for varied combinations of PAS-dependent protein-protein interactions and promoting crosstalk among signaling pathways. Previous studies report crosstalk between circadian clock proteins and the aryl hydrocarbon receptor (AhR). Activated AhR forms a heterodimer with the circadian clock protein Bmal1 and thereby functionally inhibits CLOCK/Bmal1 activity. If physiological activation of AhR through naturally occurring, endogenous ligands inhibits clock function, it seems plausible to hypothesize that decreased AhR expression releases AhR-induced inhibition of circadian rhythms. Because both AhR and the clock are important regulators of glucose metabolism, it follows that decreased AhR will also alter metabolic function. To test this hypothesis, rhythms of behavior, metabolic outputs, and circadian and metabolic gene expression were measured in AhR-deficient mice. Genetic depletion of AhR enhanced behavioral responses to changes in the light-dark cycle, increased rhythmic amplitude of circadian clock genes in the liver, and altered rhythms of glucose and insulin. This study provides evidence of AhR-induced inhibition that influences circadian rhythm amplitude.
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Chi-Castañeda, Donají, and Arturo Ortega. "The Role of Mammalian Glial Cells in Circadian Rhythm Regulation." Neural Plasticity 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/8140737.
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Circadian rhythms are biological oscillations with a period of about 24 hours. These rhythms are maintained by an innate genetically determined time-keeping system called the circadian clock. A large number of the proteins involved in the regulation of this clock are transcription factors controlling rhythmic transcription ofso-calledclock-controlled genes, which participate in a plethora of physiological functions in the organism. In the brain, several areas, besides the suprachiasmatic nucleus, harbor functional clocks characterized by a well-defined time pattern of clock gene expression. This expression rhythm is not restricted to neurons but is also present in glia, suggesting that these cells are involved in circadian rhythmicity. However, only certain glial cells fulfill the criteria to be called glial clocks, namely, to display molecular oscillators based on the canonical clock protein PERIOD, which depends on the suprachiasmatic nucleus for their synchronization. In this contribution, we summarize the current information about activity of the clock genes in glial cells, their potential role as oscillators as well as clinical implications.
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Kidd, Philip B., Michael W. Young, and Eric D. Siggia. "Temperature compensation and temperature sensation in the circadian clock." Proceedings of the National Academy of Sciences 112, no. 46 (November 2, 2015): E6284—E6292. http://dx.doi.org/10.1073/pnas.1511215112.
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All known circadian clocks have an endogenous period that is remarkably insensitive to temperature, a property known as temperature compensation, while at the same time being readily entrained by a diurnal temperature oscillation. Although temperature compensation and entrainment are defining features of circadian clocks, their mechanisms remain poorly understood. Most models presume that multiple steps in the circadian cycle are temperature-dependent, thus facilitating temperature entrainment, but then insist that the effect of changes around the cycle sums to zero to enforce temperature compensation. An alternative theory proposes that the circadian oscillator evolved from an adaptive temperature sensor: a gene circuit that responds only to temperature changes. This theory implies that temperature changes should linearly rescale the amplitudes of clock component oscillations but leave phase relationships and shapes unchanged. We show using timeless luciferase reporter measurements and Western blots against TIMELESS protein that this prediction is satisfied by the Drosophila circadian clock. We also review evidence for pathways that couple temperature to the circadian clock, and show previously unidentified evidence for coupling between the Drosophila clock and the heat-shock pathway.
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Gallardo, Amador, Aldara Molina, Helena G. Asenjo, Jordi Martorell-Marugán, Rosa Montes, Verónica Ramos-Mejia, Antonio Sanchez-Pozo, Pedro Carmona-Sáez, Lourdes Lopez-Onieva, and David Landeira. "The molecular clock protein Bmal1 regulates cell differentiation in mouse embryonic stem cells." Life Science Alliance 3, no. 5 (April 13, 2020): e201900535. http://dx.doi.org/10.26508/lsa.201900535.
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Mammals optimize their physiology to the light–dark cycle by synchronization of the master circadian clock in the brain with peripheral clocks in the rest of the tissues of the body. Circadian oscillations rely on a negative feedback loop exerted by the molecular clock that is composed by transcriptional activators Bmal1 and Clock, and their negative regulators Period and Cryptochrome. Components of the molecular clock are expressed during early development, but onset of robust circadian oscillations is only detected later during embryogenesis. Here, we have used naïve pluripotent mouse embryonic stem cells (mESCs) to study the role of Bmal1 during early development. We found that, compared to wild-type cells, Bmal1−/− mESCs express higher levels of Nanog protein and altered expression of pluripotency-associated signalling pathways. Importantly, Bmal1−/− mESCs display deficient multi-lineage cell differentiation capacity during the formation of teratomas and gastrula-like organoids. Overall, we reveal that Bmal1 regulates pluripotent cell differentiation and propose that the molecular clock is an hitherto unrecognized regulator of mammalian development.
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Pattanayek, Rekha, Jimin Wang, Tetsuya Mori, Yao Xu, Carl Hirschie Johnson, and Martin Egli. "Visualizing a Circadian Clock Protein." Molecular Cell 15, no. 3 (August 2004): 375–88. http://dx.doi.org/10.1016/j.molcel.2004.07.013.
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Pattanayek, Rekha, Jimin Wang, Tetsuya Mori, Yao Xu, Carl Hirschie Johnson, and Martin Egli. "Visualizing a Circadian Clock Protein." Molecular Cell 15, no. 5 (September 2004): 841. http://dx.doi.org/10.1016/j.molcel.2004.08.027.
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Gabryelska, Agata, Marcin Sochal, Szymon Turkiewicz, and Piotr Białasiewicz. "Relationship between HIF-1 and Circadian Clock Proteins in Obstructive Sleep Apnea Patients—Preliminary Study." Journal of Clinical Medicine 9, no. 5 (May 25, 2020): 1599. http://dx.doi.org/10.3390/jcm9051599.
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Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia and associated with the disruption of circadian rhythm. The study aimed to assess the relationship between hypoxia-inducible factor (HIF) subunits, circadian clock proteins, and polysomnography (PSG) variables, in healthy individuals and severe OSA patients. The study included 20 individuals, who underwent PSG and were divided into severe OSA group (n = 10; AHI ≥ 30) and healthy control (n = 10; AHI < 5) based on apnea-hypopnea index (AHI). All participants had their peripheral blood collected in the evening before and the morning after the PSG. HIF-1α, HIF-1β, BMAL1, CLOCK, CRY1, and PER1 protein concertation measurements were performed using ELISA. In a multivariate general linear model with the concentration of all circadian clock proteins as dependent variables, evening HIF-1α protein level was the only significant covariant (p = 0.025). Corrected models were significant for morning and evening PER1 (p = 0.008 and p = 0.006, respectively), evening (p = 0.043), and evening BMAL protein level (p = 0.046). In corrected models, evening HIF-1α protein level had an influence only on the evening PER1 protein level. Results suggest that OSA patients are at risk for developing circadian clock disruption. This process might be mediated by subunit α of HIF-1, as its increased protein level is associated with overexpression of circadian clock proteins.
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Singh, Amit, Congxin Li, Axel C. R. Diernfellner, Thomas Höfer, and Michael Brunner. "Data-driven modelling captures dynamics of the circadian clock of Neurospora crassa." PLOS Computational Biology 18, no. 8 (August 11, 2022): e1010331. http://dx.doi.org/10.1371/journal.pcbi.1010331.
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Eukaryotic circadian clocks are based on self-sustaining, cell-autonomous oscillatory feedback loops that can synchronize with the environment via recurrent stimuli (zeitgebers) such as light. The components of biological clocks and their network interactions are becoming increasingly known, calling for a quantitative understanding of their role for clock function. However, the development of data-driven mathematical clock models has remained limited by the lack of sufficiently accurate data. Here we present a comprehensive model of the circadian clock of Neurospora crassa that describe free-running oscillations in constant darkness and entrainment in light-dark cycles. To parameterize the model, we measured high-resolution time courses of luciferase reporters of morning and evening specific clock genes in WT and a mutant strain. Fitting the model to such comprehensive data allowed estimating parameters governing circadian phase, period length and amplitude, and the response of genes to light cues. Our model suggests that functional maturation of the core clock protein Frequency causes a delay in negative feedback that is critical for generating circadian rhythms.
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He, Lan, J. Austin Hamm, Alex Reddy, David Sams, Rodrigo A. Peliciari-Garcia, Graham R. McGinnis, Shannon M. Bailey, et al. "Biotinylation: a novel posttranslational modification linking cell autonomous circadian clocks with metabolism." American Journal of Physiology-Heart and Circulatory Physiology 310, no. 11 (June 1, 2016): H1520—H1532. http://dx.doi.org/10.1152/ajpheart.00959.2015.
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Circadian clocks are critical modulators of metabolism. However, mechanistic links between cell autonomous clocks and metabolic processes remain largely unknown. Here, we report that expression of the biotin transporter slc5a6 gene is decreased in hearts of two distinct genetic mouse models of cardiomyocyte-specific circadian clock disruption [i.e., cardiomyocyte-specific CLOCK mutant (CCM) and cardiomyocyte-specific BMAL1 knockout (CBK) mice]. Biotinylation is an obligate posttranslational modification for five mammalian carboxylases: acetyl-CoA carboxylase α (ACCα), ACCβ, pyruvate carboxylase (PC), methylcrotonyl-CoA carboxylase (MCC), and propionyl-CoA carboxylase (PCC). We therefore hypothesized that the cardiomyocyte circadian clock impacts metabolism through biotinylation. Consistent with decreased slc5a6 expression, biotinylation of all carboxylases is significantly decreased (10–46%) in CCM and CBK hearts. In association with decreased biotinylated ACC, oleate oxidation rates are increased in both CCM and CBK hearts. Consistent with decreased biotinylated MCC, leucine oxidation rates are significantly decreased in both CCM and CBK hearts, whereas rates of protein synthesis are increased. Importantly, feeding CBK mice with a biotin-enriched diet for 6 wk normalized myocardial 1) ACC biotinylation and oleate oxidation rates; 2) PCC/MCC biotinylation (and partially restored leucine oxidation rates); and 3) net protein synthesis rates. Furthermore, data suggest that the RRAGD/mTOR/4E-BP1 signaling axis is chronically activated in CBK and CCM hearts. Finally we report that the hepatocyte circadian clock also regulates both slc5a6 expression and protein biotinylation in the liver. Collectively, these findings suggest that biotinylation is a novel mechanism by which cell autonomous circadian clocks influence metabolic pathways.
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Kippert, Fred. "Cellular signalling and the complexity of biological timing: insights from the ultradian clock of Schizosaccharomyces pombe." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1415 (November 29, 2001): 1725–33. http://dx.doi.org/10.1098/rstb.2001.0935.
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The molecular bases of circadian clocks are complex and cannot be sufficiently explained by the relatively simple feedback loops, based on transcription and translation, of current models. The existence of additional oscillators has been demonstrated experimentally, but their mechanism(s) have so far resisted elucidation and any universally conserved clock components have yet to be identified. The fission yeast, Schizosaccharomyces pombe , as a simple and well–characterized eukaryote, is a useful model organism in the investigation of many aspects of cell regulation. In fast–growing cells of the yeast an ultradian clock operates, which can serve as a model system to analyse clock complexity. This clock shares strict period homeostasis and efficient entrainment with circadian clocks but, because of its short period of 30 min, mechanisms other than a transcription/translation–based feedback loop must be working. An initial systematic screen involving over 200 deletion mutants has shown that major cellular signalling pathways (calcium/phosphoinositide, mitogen–activated protein kinase and cAMP/protein kinase A) are crucial for the normal functioning of this ultradian clock. A comparative examination of the role of cellular signalling pathways in the S.pombe ultradian clock and in the circadian timekeeping of different eukaryotes may indicate common principles in biological timing processes that are universally conserved amongst eukaryotes.
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Liu, Zhenxing, Christopher P. Selby, Yanyan Yang, Laura A. Lindsey-Boltz, Xuemei Cao, Khagani Eynullazada, and Aziz Sancar. "Circadian regulation of c-MYC in mice." Proceedings of the National Academy of Sciences 117, no. 35 (August 19, 2020): 21609–17. http://dx.doi.org/10.1073/pnas.2011225117.
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The circadian clock is a global regulatory mechanism that controls the expression of 50 to 80% of transcripts in mammals. Some of the genes controlled by the circadian clock are oncogenes or tumor suppressors. Among theseMychas been the focus of several studies which have investigated the effect of clock genes and proteins onMyctranscription and MYC protein stability. Other studies have focused on effects ofMycmutation or overproduction on the circadian clock in comparison to their effects on cell cycle progression and tumorigenesis. Here we have used mice with mutations in the essential clock genesBmal1,Cry1,andCry2to gain further insight into the effect of the circadian clock on this important oncogene/oncoprotein and tumorigenesis. We find that mutation of bothCry1andCry2, which abolishes the negative arm of the clock transcription–translation feedback loop (TTFL), causes down-regulation of c-MYC, and mutation ofBmal1,which abolishes the positive arm of TTFL, causes up-regulation of the c-MYC protein level in mouse spleen. These findings must be taken into account in models of the clock disruption–cancer connection.
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Umemura, Yasuhiro, Izumi Maki, Yoshiki Tsuchiya, Nobuya Koike, and Kazuhiro Yagita. "Human Circadian Molecular Oscillation Development Using Induced Pluripotent Stem Cells." Journal of Biological Rhythms 34, no. 5 (August 2019): 525–32. http://dx.doi.org/10.1177/0748730419865436.
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The mammalian circadian clock, which coordinates various physiological functions, develops gradually during ontogeny. Recently, we have reported the posttranscriptional suppression of CLOCK protein expression as a key mechanism of the emergence of the circadian clock during mouse development. However, whether a common mechanism regulates the development of the human circadian clock remains unclear. In the present study, we show that human induced pluripotent stem cells (iPSCs) have no discernible circadian molecular oscillation. In addition, in vitro differentiation culture of human iPSCs required a longer duration than that required in mouse for the emergence of circadian oscillations. The expression of CLOCK protein in undifferentiated human iPSCs was posttranscriptionally suppressed despite the expression of CLOCK mRNA, which is consistent with our previous observations in mouse embryonic stem cells, iPSCs, and early mouse embryos. These results suggest that CLOCK protein expressions could be posttranscriptionally suppressed in the early developmental stage not only in mice but also in humans.
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Forsyth, Christopher B., Robin M. Voigt, Maliha Shaikh, Yueming Tang, Arthur I. Cederbaum, Fred W. Turek, and Ali Keshavarzian. "Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability." American Journal of Physiology-Gastrointestinal and Liver Physiology 305, no. 2 (July 15, 2013): G185—G195. http://dx.doi.org/10.1152/ajpgi.00354.2012.
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We have shown that alcohol increases Caco-2 intestinal epithelial cell monolayer permeability in vitro by inducing the expression of redox-sensitive circadian clock proteins CLOCK and PER2 and that these proteins are necessary for alcohol-induced hyperpermeability. We hypothesized that alcohol metabolism by intestinal Cytochrome P450 isoform 2E1 (CYP2E1) could alter circadian gene expression ( Clock and Per2), resulting in alcohol-induced hyperpermeability. In vitro Caco-2 intestinal epithelial cells were exposed to alcohol, and CYP2E1 protein, activity, and mRNA were measured. CYP2E1 expression was knocked down via siRNA and alcohol-induced hyperpermeability, and CLOCK and PER2 protein expression were measured. Caco-2 cells were also treated with alcohol or H2O2 with or without N-acetylcysteine (NAC) anti-oxidant, and CLOCK and PER2 proteins were measured at 4 or 2 h. In vivo Cyp2e1 protein and mRNA were also measured in colon tissue from alcohol-fed mice. Alcohol increased CYP2E1 protein by 93% and enzyme activity by 69% in intestinal cells in vitro. Alcohol feeding also increased mouse colonic Cyp2e1 protein by 73%. mRNA levels of Cyp2e1 were not changed by alcohol in vitro or in mouse intestine. siRNA knockdown of CYP2E1 in Caco-2 cells prevented alcohol-induced hyperpermeability and induction of CLOCK and PER2 proteins. Alcohol-induced and H2O2-induced increases in intestinal cell CLOCK and PER2 were significantly inhibited by treatment with NAC. We concluded that our data support a novel role for intestinal CYP2E1 in alcohol-induced intestinal hyperpermeability via a mechanism involving CYP2E1-dependent induction of oxidative stress and upregulation of circadian clock proteins CLOCK and PER2.
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Mekbib, Tsedey, Ting-Chung Suen, Aisha Rollins-Hairston, and Jason P. DeBruyne. "The E3 Ligases Spsb1 and Spsb4 Regulate RevErbα Degradation and Circadian Period." Journal of Biological Rhythms 34, no. 6 (October 14, 2019): 610–21. http://dx.doi.org/10.1177/0748730419878036.
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The time-dependent degradation of core circadian clock proteins is essential for the proper functioning of circadian timekeeping mechanisms that drive daily rhythms in gene expression and, ultimately, an organism’s physiology. The ubiquitin proteasome system plays a critical role in regulating the stability of most proteins, including the core clock components. Our laboratory developed a cell-based functional screen to identify ubiquitin ligases that degrade any protein of interest and have started screening for those ligases that degrade circadian clock proteins. This screen identified Spsb4 as a putative novel E3 ligase for RevErbα. In this article, we further investigate the role of Spsb4 and its paralogs in RevErbα stability and circadian rhythmicity. Our results indicate that the paralogs Spsb1 and Spsb4, but not Spsb2 and Spsb3, can interact with and facilitate RevErbα ubiquitination and degradation and regulate circadian clock periodicity.
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O’Grady, Joseph F., Laura S. Hoelters, Martin T. Swain, and David C. Wilcockson. "Identification and temporal expression of putative circadian clock transcripts in the amphipod crustaceanTalitrus saltator." PeerJ 4 (October 5, 2016): e2555. http://dx.doi.org/10.7717/peerj.2555.
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BackgroundTalitrus saltatoris an amphipod crustacean that inhabits the supralittoral zone on sandy beaches in the Northeast Atlantic and Mediterranean.T. saltatorexhibits endogenous locomotor activity rhythms and time-compensated sun and moon orientation, both of which necessitate at least one chronometric mechanism. Whilst their behaviour is well studied, currently there are no descriptions of the underlying molecular components of a biological clock in this animal, and very few in other crustacean species.MethodsWe harvested brain tissue from animals expressing robust circadian activity rhythms and used homology cloning and Illumina RNAseq approaches to sequence and identify the core circadian clock and clock-related genes in these samples. We assessed the temporal expression of these genes in time-course samples from rhythmic animals using RNAseq.ResultsWe identified a comprehensive suite of circadian clock gene homologues inT. saltatorincluding the ‘core’ clock genesperiod(Talper),cryptochrome 2(Talcry2),timeless(Taltim),clock(Talclk), andbmal1(Talbmal1). In addition we describe the sequence and putative structures of 23 clock-associated genes including two unusual, extended isoforms of pigment dispersing hormone (Talpdh). We examined time-course RNAseq expression data, derived from tissues harvested from behaviourally rhythmic animals, to reveal rhythmic expression of these genes with approximately circadian period inTalperandTalbmal1. Of the clock-related genes,casein kinase IIβ(TalckIIβ),ebony(Talebony),jetlag(Taljetlag),pigment dispensing hormone(Talpdh),protein phosphatase 1(Talpp1),shaggy(Talshaggy),sirt1(Talsirt1), sirt7 (Talsirt7) and supernumerary limbs (Talslimb) show temporal changes in expression.DiscussionWe report the sequences of principle genes that comprise the circadian clock ofT. saltatorand highlight the conserved structural and functional domains of their deduced cognate proteins. Our sequencing data contribute to the growing inventory of described comparative clocks. Expression profiling of the identified clock genes illuminates tantalising targets for experimental manipulation to elucidate the molecular and cellular control of clock-driven phenotypes in this crustacean.
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Kelly, Mia N., Danelle N. Smith, Michael D. Sunshine, Ashley Ross, Xiping Zhang, Michelle L. Gumz, Karyn A. Esser, and Gordon S. Mitchell. "Circadian clock genes and respiratory neuroplasticity genes oscillate in the phrenic motor system." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 318, no. 6 (June 1, 2020): R1058—R1067. http://dx.doi.org/10.1152/ajpregu.00010.2020.
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Circadian rhythms are endogenous and entrainable daily patterns of physiology and behavior. Molecular mechanisms underlie circadian rhythms, characterized by an ~24-h pattern of gene expression of core clock genes. Although it has long been known that breathing exhibits circadian rhythms, little is known concerning clock gene expression in any element of the neuromuscular system controlling breathing. Furthermore, we know little concerning gene expression necessary for specific respiratory functions, such as phrenic motor plasticity. Thus, we tested the hypotheses that transcripts for clock genes ( Bmal1, Clock, Per1, and Per2) and molecules necessary for phrenic motor plasticity ( Htr2a, Htr2b, Bdnf, and Ntrk2) oscillate in regions critical for phrenic/diaphragm motor function via RT-PCR. Tissues were collected from male Sprague-Dawley rats entrained to a 12-h light-dark cycle at 4 zeitgeber times (ZT; n = 8 rats/group): ZT5, ZT11, ZT17, and ZT23; ZT0 = lights on. Here, we demonstrate that 1) circadian clock genes ( Bmal1, Clock, Per1, and Per2) oscillate in regions critical for phrenic/diaphragm function, including the caudal medulla, ventral C3–C5 cervical spinal cord, and diaphragm; 2) the clock protein BMAL1 is localized within CtB-labeled phrenic motor neurons; 3) genes necessary for intermittent hypoxia-induced phrenic/diaphragm motor plasticity ( Htr2b and Bdnf) oscillate in the caudal medulla and ventral C3–C5 spinal cord; and 4) there is higher intensity of immunofluorescent BDNF protein within phrenic motor neurons at ZT23 compared with ZT11 ( n = 11 rats/group). These results suggest local circadian clocks exist in the phrenic motor system and confirm the potential for local circadian regulation of neuroplasticity and other elements of the neural network controlling breathing.
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Shen, Yang, Mehari Endale, Wei Wang, Andrew R. Morris, Lauren J. Francey, Rachel L. Harold, David W. Hammers, et al. "NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1." PLOS Genetics 17, no. 11 (November 22, 2021): e1009933. http://dx.doi.org/10.1371/journal.pgen.1009933.
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In mammals, the circadian clock coordinates cell physiological processes including inflammation. Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the clock is not well understood. Here, we investigated the role of the proinflammatory transcription factor NF-κB in regulating clock function. Using a combination of genetic and pharmacological approaches, we show that perturbation of the canonical NF-κB subunit RELA in the human U2OS cellular model altered core clock gene expression. While RELA activation shortened period length and dampened amplitude, its inhibition lengthened period length and caused amplitude phenotypes. NF-κB perturbation also altered circadian rhythms in the master suprachiasmatic nucleus (SCN) clock and locomotor activity behavior under different light/dark conditions. We show that RELA, like the clock repressor CRY1, repressed the transcriptional activity of BMAL1/CLOCK at the circadian E-box cis-element. Biochemical and biophysical analysis showed that RELA binds to the transactivation domain of BMAL1. These data support a model in which NF-kB competes with CRY1 and coactivator CBP/p300 for BMAL1 binding to affect circadian transcription. This is further supported by chromatin immunoprecipitation analysis showing that binding of RELA, BMAL1 and CLOCK converges on the E-boxes of clock genes. Taken together, these data support a significant role for NF-κB in directly regulating the circadian clock and highlight mutual regulation between the circadian and inflammatory pathways.
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Umemura, Yasuhiro, Nobuya Koike, Munehiro Ohashi, Yoshiki Tsuchiya, Qing Jun Meng, Yoichi Minami, Masayuki Hara, Moe Hisatomi, and Kazuhiro Yagita. "Involvement of posttranscriptional regulation of Clock in the emergence of circadian clock oscillation during mouse development." Proceedings of the National Academy of Sciences 114, no. 36 (August 21, 2017): E7479—E7488. http://dx.doi.org/10.1073/pnas.1703170114.
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Circadian clock oscillation emerges in mouse embryo in the later developmental stages. Although circadian clock development is closely correlated with cellular differentiation, the mechanisms of its emergence during mammalian development are not well understood. Here, we demonstrate an essential role of the posttranscriptional regulation of Clock subsequent to the cellular differentiation for the emergence of circadian clock oscillation in mouse fetal hearts and mouse embryonic stem cells (ESCs). In mouse fetal hearts, no apparent oscillation of cell-autonomous molecular clock was detectable around E10, whereas oscillation was clearly visible in E18 hearts. Temporal RNA-sequencing analysis using mouse fetal hearts reveals many fewer rhythmic genes in E10–12 hearts (63, no core circadian genes) than in E17–19 hearts (483 genes), suggesting the lack of functional circadian transcriptional/translational feedback loops (TTFLs) of core circadian genes in E10 mouse fetal hearts. In both ESCs and E10 embryos, CLOCK protein was absent despite the expression of Clock mRNA, which we showed was due to Dicer/Dgcr8-dependent translational suppression of CLOCK. The CLOCK protein is required for the discernible molecular oscillation in differentiated cells, and the posttranscriptional regulation of Clock plays a role in setting the timing for the emergence of the circadian clock oscillation during mammalian development.
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Kon, Naohiro, Hsin-tzu Wang, Yoshiaki S. Kato, Kyouhei Uemoto, Naohiro Kawamoto, Koji Kawasaki, Ryosuke Enoki, et al. "Na+/Ca2+ exchanger mediates cold Ca2+ signaling conserved for temperature-compensated circadian rhythms." Science Advances 7, no. 18 (April 2021): eabe8132. http://dx.doi.org/10.1126/sciadv.abe8132.
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Circadian rhythms are based on biochemical oscillations generated by clock genes/proteins, which independently evolved in animals, fungi, plants, and cyanobacteria. Temperature compensation of the oscillation speed is a common feature of the circadian clocks, but the evolutionary-conserved mechanism has been unclear. Here, we show that Na+/Ca2+ exchanger (NCX) mediates cold-responsive Ca2+ signaling important for the temperature-compensated oscillation in mammalian cells. In response to temperature decrease, NCX elevates intracellular Ca2+, which activates Ca2+/calmodulin-dependent protein kinase II and accelerates transcriptional oscillations of clock genes. The cold-responsive Ca2+ signaling is conserved among mice, Drosophila, and Arabidopsis. The mammalian cellular rhythms and Drosophila behavioral rhythms were severely attenuated by NCX inhibition, indicating essential roles of NCX in both temperature compensation and autonomous oscillation. NCX also contributes to the temperature-compensated transcriptional rhythms in cyanobacterial clock. Our results suggest that NCX-mediated Ca2+ signaling is a common mechanism underlying temperature-compensated circadian rhythms both in eukaryotes and prokaryotes.
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Hassan, Azka, Jamil Ahmad, Hufsah Ashraf, and Amjad Ali. "Modeling and analysis of the impacts of jet lag on circadian rhythm and its role in tumor growth." PeerJ 6 (June 6, 2018): e4877. http://dx.doi.org/10.7717/peerj.4877.
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Circadian rhythms maintain a 24 h oscillation pattern in metabolic, physiological and behavioral processes in all living organisms. Circadian rhythms are organized as biochemical networks located in hypothalamus and peripheral tissues. Rhythmicity in the expression of circadian clock genes plays a vital role in regulating the process of cell division and DNA damage control. The oncogenic protein, MYC and the tumor suppressor, p53 are directly influenced by the circadian clock. Jet lag and altered sleep/wake schedules prominently affect the expression of molecular clock genes. This study is focused on developing a Petri net model to analyze the impacts of long term jet lag on the circadian clock and its probable role in tumor progression. The results depict that jet lag disrupts the normal rhythmic behavior and expression of the circadian clock proteins. This disruption leads to persistent expression of MYC and suppressed expression of p53. Thus, it is inferred that jet lag altered circadian clock negatively affects the expressions of cell cycle regulatory genes and contribute in uncontrolled proliferation of tumor cells.
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Goda, Tadahiro, Brandi Sharp, and Herman Wijnen. "Temperature-dependent resetting of the molecular circadian oscillator in Drosophila." Proceedings of the Royal Society B: Biological Sciences 281, no. 1793 (October 22, 2014): 20141714. http://dx.doi.org/10.1098/rspb.2014.1714.
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Circadian clocks responsible for daily time keeping in a wide range of organisms synchronize to daily temperature cycles via pathways that remain poorly understood. To address this problem from the perspective of the molecular oscillator, we monitored temperature-dependent resetting of four of its core components in the fruitfly Drosophila melanogaster : the transcripts and proteins for the clock genes period ( per ) and timeless ( tim ). The molecular circadian cycle in adult heads exhibited parallel responses to temperature-mediated resetting at the levels of per transcript, tim transcript and TIM protein. Early phase adjustment specific to per transcript rhythms was explained by clock-independent temperature-driven transcription of per . The cold-induced expression of Drosophila per contrasts with the previously reported heat-induced regulation of mammalian Period 2 . An altered and more readily re-entrainable temperature-synchronized circadian oscillator that featured temperature-driven per transcript rhythms and phase-shifted TIM and PER protein rhythms was found for flies of the ‘Tim 4’ genotype, which lacked daily tim transcript oscillations but maintained post-transcriptional temperature entrainment of tim expression. The accelerated molecular and behavioural temperature entrainment observed for Tim 4 flies indicates that clock-controlled tim expression constrains the rate of temperature cycle-mediated circadian resetting.
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Tabuloc, Christine A., Yao D. Cai, Rosanna S. Kwok, Elizabeth C. Chan, Sergio Hidalgo, and Joanna C. Chiu. "CLOCK and TIMELESS regulate rhythmic occupancy of the BRAHMA chromatin-remodeling protein at clock gene promoters." PLOS Genetics 19, no. 2 (February 21, 2023): e1010649. http://dx.doi.org/10.1371/journal.pgen.1010649.
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Circadian clock and chromatin-remodeling complexes are tightly intertwined systems that regulate rhythmic gene expression. The circadian clock promotes rhythmic expression, timely recruitment, and/or activation of chromatin remodelers, while chromatin remodelers regulate accessibility of clock transcription factors to the DNA to influence expression of clock genes. We previously reported that the BRAHMA (BRM) chromatin-remodeling complex promotes the repression of circadian gene expression in Drosophila. In this study, we investigated the mechanisms by which the circadian clock feeds back to modulate daily BRM activity. Using chromatin immunoprecipitation, we observed rhythmic BRM binding to clock gene promoters despite constitutive BRM protein expression, suggesting that factors other than protein abundance are responsible for rhythmic BRM occupancy at clock-controlled loci. Since we previously reported that BRM interacts with two key clock proteins, CLOCK (CLK) and TIMELESS (TIM), we examined their effect on BRM occupancy to the period (per) promoter. We observed reduced BRM binding to the DNA in clk null flies, suggesting that CLK is involved in enhancing BRM occupancy to initiate transcriptional repression at the conclusion of the activation phase. Additionally, we observed reduced BRM binding to the per promoter in flies overexpressing TIM, suggesting that TIM promotes BRM removal from DNA. These conclusions are further supported by elevated BRM binding to the per promoter in flies subjected to constant light and experiments in Drosophila tissue culture in which the levels of CLK and TIM are manipulated. In summary, this study provides new insights into the reciprocal regulation between the circadian clock and the BRM chromatin-remodeling complex.
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Collett, Michael A., Jay C. Dunlap, and Jennifer J. Loros. "Circadian Clock-Specific Roles for the Light Response Protein WHITE COLLAR-2." Molecular and Cellular Biology 21, no. 8 (April 15, 2001): 2619–28. http://dx.doi.org/10.1128/mcb.21.8.2619-2628.2001.
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ABSTRACT To understand the role of white collar-2 in theNeurospora circadian clock, we examined alleles ofwc-2 thought to encode partially functional proteins. We found that wc-2 allele ER24 contained a conservative mutation in the zinc finger. This mutation results in reduced levels of circadian rhythm-critical clock gene products, frq mRNA and FRQ protein, and in a lengthened period of the circadian clock. In addition, this mutation altered a second canonical property of the clock, temperature compensation: as temperature increased, period length decreased substantially. This temperature compensation defect correlated with a temperature-dependent increase in overall FRQ protein levels, with the relative increase being greater in wc-2(ER24) than in wild type, while overall frq mRNA levels were largely unaltered by temperature. We suggest that this temperature-dependent increase in FRQ levels partially rescues the lowered levels of FRQ resulting from the wc-2 (ER24) defect, yielding a shorter period at higher temperatures. Thus, normal activity of the essential clock component WC-2, a positive regulator offrq, is critical for establishing period length and temperature compensation in this circadian system.
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Paijmans, Joris, Mark Bosman, Pieter Rein ten Wolde, and David K. Lubensky. "Discrete gene replication events drive coupling between the cell cycle and circadian clocks." Proceedings of the National Academy of Sciences 113, no. 15 (March 28, 2016): 4063–68. http://dx.doi.org/10.1073/pnas.1507291113.
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Many organisms possess both a cell cycle to control DNA replication and a circadian clock to anticipate changes between day and night. In some cases, these two rhythmic systems are known to be coupled by specific, cross-regulatory interactions. Here, we use mathematical modeling to show that, additionally, the cell cycle generically influences circadian clocks in a nonspecific fashion: The regular, discrete jumps in gene-copy number arising from DNA replication during the cell cycle cause a periodic driving of the circadian clock, which can dramatically alter its behavior and impair its function. A clock built on negative transcriptional feedback either phase-locks to the cell cycle, so that the clock period tracks the cell division time, or exhibits erratic behavior. We argue that the cyanobacterium Synechococcus elongatus has evolved two features that protect its clock from such disturbances, both of which are needed to fully insulate it from the cell cycle and give it its observed robustness: a phosphorylation-based protein modification oscillator, together with its accompanying push–pull read-out circuit that responds primarily to the ratios of different phosphoform concentrations, makes the clock less susceptible to perturbations in protein synthesis; the presence of multiple, asynchronously replicating copies of the same chromosome diminishes the effect of replicating any single copy of a gene.
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Sen, Liu, and Song Liu. "Evolution Analysis of the Circadian Clock Protein KaiB." Advanced Materials Research 647 (January 2013): 391–95. http://dx.doi.org/10.4028/www.scientific.net/amr.647.391.
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Regulation of daily physiological functions with approximate a 24-hour periodicity, or circadian rhythms, is a characteristic of eukaryotes. So far, cyanobacteria are only known prokaryotes reported to possess circadian rhythmicity. The circadian system in cyanobacteria comprises both a post-translational oscillator (PTO) and a transcriptional/translational feedback loop (TTFL). The PTO can be reconstituted in vitro with three purified proteins (KaiA, KaiB, and KaiC) with the existence of ATP. Phase of the nanoclockwork has been associated with the phosphorylation states of KaiC, with KaiA promoting the phosphorylation of KaiC, and KaiB de-phosphorylating KaiC. Here we studied the evolution of the KaiB protein. The result will be helpful in understanding the evolution of the circadian clock system.
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Larrondo, L. F., C. Olivares-Yanez, C. L. Baker, J. J. Loros, and J. C. Dunlap. "Decoupling circadian clock protein turnover from circadian period determination." Science 347, no. 6221 (January 29, 2015): 1257277. http://dx.doi.org/10.1126/science.1257277.
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Kim, Jin A., Donghwan Shim, Shipra Kumari, Ha-eun Jung, Ki-Hong Jung, Heesu Jeong, Woe-Yeon Kim, Soo In Lee, and Mi-Jeong Jeong. "Transcriptome Analysis of Diurnal Gene Expression in Chinese Cabbage." Genes 10, no. 2 (February 11, 2019): 130. http://dx.doi.org/10.3390/genes10020130.
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Plants have developed timing mechanisms that enable them to maintain synchrony with daily environmental events. These timing mechanisms, i.e., circadian clocks, include transcriptional/translational feedback loops that drive 24 h transcriptional rhythms, which underlie oscillations in protein abundance, thus mediating circadian rhythms of behavior, physiology, and metabolism. Circadian clock genes have been investigated in the diploid model plant Arabidopsis thaliana. Crop plants with polyploid genomes—such as Brassica species—have multiple copies of some clock-related genes. Over the last decade, numerous studies have been aimed at identifying and understanding the function of paralogous genes with conserved sequences, or those that diverged during evolution. Brassica rapa’s triplicate genomes retain sequence-level collinearity with Arabidopsis. In this study, we used RNA sequencing (RNAseq) to profile the diurnal transcriptome of Brassica rapa seedlings. We identified candidate paralogs of circadian clock-related genes and assessed their expression levels. These genes and their related traits that modulate the diurnal rhythm of gene expression contribute to the adaptation of crop cultivars. Our findings will contribute to the mechanistic study of circadian clock regulation inherent in polyploidy genome crops, which differ from those of model plants, and thus will be useful for future breeding studies using clock genes.
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Ma, Huan, Luyao Li, Jie Yan, Yin Zhang, Xiaohong Ma, Yunzhen Li, Yu Yuan, Xiaolin Yang, Ling Yang, and Jinhu Guo. "The Resonance and Adaptation of Neurospora crassa Circadian and Conidiation Rhyth ms to Short Light-Dark Cycles." Journal of Fungi 8, no. 1 (December 29, 2021): 27. http://dx.doi.org/10.3390/jof8010027.
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Circadian clocks control the physiological and behavioral rhythms to adapt to the environment with a period of ~24 h. However, the influences and mechanisms of the extreme light/dark cycles on the circadian clock remain unclear. We showed that, in Neurospora crassa, both the growth and the microconidia production contribute to adaptation in LD12:12 (12 h light/12 h dark, periodically). Mathematical modeling and experiments demonstrate that in short LD cycles, the expression of the core clock protein FREQUENCY was entrained to the LD cycles when LD > 3:3 while it free ran when T ≤ LD3:3. The conidial rhythmicity can resonate with a series of different LD conditions. Moreover, we demonstrate that the existence of unknown blue light photoreceptor(s) and the circadian clock might promote the conidiation rhythms that resonate with the environment. The ubiquitin E3 ligase FWD-1 and the previously described CRY-dependent oscillator system were implicated in regulating conidiation under short LD conditions. These findings shed new light on the resonance of Neurospora circadian clock and conidiation rhythms to short LD cycles, which may benefit the understandings of both the basic regulatory aspects of circadian clock and the adaptation of physiological rhythms to the extreme conditions.
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Lim, Chunghun, Jongbin Lee, Changtaek Choi, Juwon Kim, Eunjin Doh, and Joonho Choe. "Functional Role of CREB-Binding Protein in the Circadian Clock System of Drosophila melanogaster." Molecular and Cellular Biology 27, no. 13 (April 23, 2007): 4876–90. http://dx.doi.org/10.1128/mcb.02155-06.
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ABSTRACT Rhythmic histone acetylation underlies the oscillating expression of clock genes in the mammalian circadian clock system. Cellular factors that contain histone acetyltransferase and histone deacetylase activity have been implicated in these processes by direct interactions with clock genes, but their functional relevance remains to be assessed by use of appropriate animal models. Here, using transgenic fly models, we show that CREB-binding protein (CBP) participates in the transcriptional regulation of the Drosophila CLOCK/CYCLE (dCLK/CYC) heterodimer. CBP knockdown in pigment dispersing factor-expressing cells lengthens the period of adult locomotor rhythm with the prolonged expression of period and timeless genes, while CBP overexpression in timeless-expressing cells causes arrhythmic circadian behaviors with the impaired expression of these dCLK/CYC-induced clock genes. In contrast to the mammalian circadian clock system, CBP overexpression attenuates the transcriptional activity of the dCLK/CYC heterodimer in cultured cells, possibly by targeting the PER-ARNT-SIM domain of dCLK. Our data suggest that the Drosophila circadian clock system has evolved a distinct mechanism to tightly regulate the robust transcriptional potency of the dCLK/CYC heterodimer.
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Ray, Sandipan, Radoslaw Lach, Kate J. Heesom, Utham K. Valekunja, Vesela Encheva, Ambrosius P. Snijders, and Akhilesh B. Reddy. "Phenotypic proteomic profiling identifies a landscape of targets for circadian clock–modulating compounds." Life Science Alliance 2, no. 6 (December 2019): e201900603. http://dx.doi.org/10.26508/lsa.201900603.
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Determining the exact targets and mechanisms of action of drug molecules that modulate circadian rhythms is critical to develop novel compounds to treat clock-related disorders. Here, we have used phenotypic proteomic profiling (PPP) to systematically determine molecular targets of four circadian period–lengthening compounds in human cells. We demonstrate that the compounds cause similar changes in phosphorylation and activity of several proteins and kinases involved in vital pathways, including MAPK, NGF, B-cell receptor, AMP-activated protein kinases (AMPKs), and mTOR signaling. Kinome profiling further indicated inhibition of CKId, ERK1/2, CDK2/7, TNIK, and MST4 kinases as a common mechanism of action for these clock-modulating compounds. Pharmacological or genetic inhibition of several convergent kinases lengthened circadian period, establishing them as novel circadian targets. Finally, thermal stability profiling revealed binding of the compounds to clock regulatory kinases, signaling molecules, and ubiquitination proteins. Thus, phenotypic proteomic profiling defines novel clock effectors that could directly inform precise therapeutic targeting of the circadian system in humans.
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McWatters, Harriet. "Pace of life: Complexity at the heart of the plant clock." Biochemist 26, no. 1 (February 1, 2004): 15–17. http://dx.doi.org/10.1042/bio02601015.
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Circadian rhythms are found in most organisms. They are endogenous rhythms of activity, hormone production or gene expression with a cycle length of approximately 24 hours. A central clock, whose principle role appears to be co-ordinating internal rhythms with the daily rhythm of day and night (Figure 1) controls the different observed rhythms in a single organism. In animals, fungi and cyanobacteria, this circadian clock is formed from loops of negative regulation of gene and protein expression1. Whether this is also true of plant clocks is the subject of some current debate.
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Doruk, Yagmur Umay, Darya Yarparvar, Yasemin Kubra Akyel, Seref Gul, Ali Cihan Taskin, Fatma Yilmaz, Ibrahim Baris, et al. "A CLOCK-binding small molecule disrupts the interaction between CLOCK and BMAL1 and enhances circadian rhythm amplitude." Journal of Biological Chemistry 295, no. 11 (February 4, 2020): 3518–31. http://dx.doi.org/10.1074/jbc.ra119.011332.
Full textAbstract:
Proper function of many physiological processes requires a robust circadian clock. Disruptions of the circadian clock can result in metabolic diseases, mood disorders, and accelerated aging. Therefore, identifying small molecules that specifically modulate regulatory core clock proteins may potentially enable better management of these disorders. In this study, we applied a structure-based molecular-docking approach to find small molecules that specifically bind to the core circadian regulator, the transcription factor circadian locomotor output cycles kaput (CLOCK). We identified 100 candidate molecules by virtual screening of ∼2 million small molecules for those predicted to bind closely to the interface in CLOCK that interacts with its transcriptional co-regulator, Brain and muscle Arnt-like protein-1 (BMAL1). Using a mammalian two-hybrid system, real-time monitoring of circadian rhythm in U2OS cells, and various biochemical assays, we tested these compounds experimentally and found one, named CLK8, that specifically bound to and interfered with CLOCK activity. We show that CLK8 disrupts the interaction between CLOCK and BMAL1 and interferes with nuclear translocation of CLOCK both in vivo and in vitro. Results from further experiments indicated that CLK8 enhances the amplitude of the cellular circadian rhythm by stabilizing the negative arm of the transcription/translation feedback loop without affecting period length. Our results reveal CLK8 as a tool for further studies of CLOCK's role in circadian rhythm amplitude regulation and as a potential candidate for therapeutic development to manage disorders associated with dampened circadian rhythms.
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DeBruyne, Jason P., Julie E. Baggs, Trey K. Sato, and John B. Hogenesch. "Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock." Proceedings of the National Academy of Sciences 112, no. 40 (September 21, 2015): 12420–25. http://dx.doi.org/10.1073/pnas.1501204112.
Full textAbstract:
Regulated degradation of proteins by the proteasome is often critical to their function in dynamic cellular pathways. The molecular clock underlying mammalian circadian rhythms relies on the rhythmic expression and degradation of its core components. However, because the tools available for identifying the mechanisms underlying the degradation of a specific protein are limited, the mechanisms regulating clock protein degradation are only beginning to be elucidated. Here we describe a cell-based functional screening approach designed to quickly identify the ubiquitin E3 ligases that induce the degradation of potentially any protein of interest. We screened the nuclear hormone receptor RevErbα (Nr1d1), a key constituent of the mammalian circadian clock, for E3 ligases that regulate its stability and found Seven in absentia2 (Siah2) to be a key regulator of RevErbα stability. Previously implicated in hypoxia signaling, Siah2 overexpression destabilizes RevErbα/β, and siRNA depletion of Siah2 stabilizes endogenous RevErbα. Moreover, Siah2 depletion delays circadian degradation of RevErbα and lengthens period length. These results demonstrate the utility of functional screening approaches for identifying regulators of protein stability and reveal Siah2 as a previously unidentified circadian clockwork regulator that mediates circadian RevErbα turnover.
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Narasimamurthy, Rajesh, Sabrina R. Hunt, Yining Lu, Jean-Michel Fustin, Hitoshi Okamura, Carrie L. Partch, Daniel B. Forger, Jae Kyoung Kim, and David M. Virshup. "CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch." Proceedings of the National Academy of Sciences 115, no. 23 (May 21, 2018): 5986–91. http://dx.doi.org/10.1073/pnas.1721076115.
Full textAbstract:
Multisite phosphorylation of the PERIOD 2 (PER2) protein is the key step that determines the period of the mammalian circadian clock. Previous studies concluded that an unidentified kinase is required to prime PER2 for subsequent phosphorylation by casein kinase 1 (CK1), an essential clock component that is conserved from algae to humans. These subsequent phosphorylations stabilize PER2, delay its degradation, and lengthen the period of the circadian clock. Here, we perform a comprehensive biochemical and biophysical analysis of mouse PER2 (mPER2) priming phosphorylation and demonstrate, surprisingly, that CK1δ/ε is indeed the priming kinase. We find that both CK1ε and a recently characterized CK1δ2 splice variant more efficiently prime mPER2 for downstream phosphorylation in cells than the well-studied splice variant CK1δ1. While CK1 phosphorylation of PER2 was previously shown to be robust to changes in the cellular environment, our phosphoswitch mathematical model of circadian rhythms shows that the CK1 carboxyl-terminal tail can allow the period of the clock to be sensitive to cellular signaling. These studies implicate the extreme carboxyl terminus of CK1 as a key regulator of circadian timing.
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Cal-Kayitmazbatir, Sibel, Lauren J. Francey, Yool Lee, Andrew C. Liu, and John B. Hogenesch. "PSMD11 modulates circadian clock function through PER and CRY nuclear translocation." PLOS ONE 18, no. 3 (March 24, 2023): e0283463. http://dx.doi.org/10.1371/journal.pone.0283463.
Full textAbstract:
The molecular circadian clock is regulated by a transcriptional translational feedback loop. However, the post-translational control mechanisms are less understood. The NRON complex is a large ribonucleoprotein complex, consisting of a lncRNA and several proteins. Components of the complex play a distinct role in regulating protein phosphorylation, synthesis, stability, and translocation in cellular processes. This includes the NFAT and the circadian clock pathway. PSMD11 is a component of the NRON complex and a lid component of the 26S proteasome. Among the PSMD family members, PSMD11 has a more specific role in circadian clock function. Here, we used cell and biochemical approaches and characterized the role of PSMD11 in regulating the stability and nuclear translocation of circadian clock proteins. We used size exclusion chromatography to enrich the NRON complex in the cytosolic and nuclear fractions. More specifically, PSMD11 knockdown affected the abundance of PER2 and CRY2 proteins and the nuclear translocation of CRY1. This changed the relative abundance of CRY1 and CRY2 in the nucleus. Thus, this work defines the role of PSMD11 in the NRON complex regulating the nuclear translocation of circadian repressors, thereby enabling cellular circadian oscillations.
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Zečević, Ksenija, Nataša Popović, Aleksandra Vuksanović Božarić, Mihailo Vukmirović, Manfredi Rizzo, and Emir Muzurović. "Timing Is Important—Management of Metabolic Syndrome According to the Circadian Rhythm." Biomedicines 11, no. 4 (April 13, 2023): 1171. http://dx.doi.org/10.3390/biomedicines11041171.
Full textAbstract:
Physiological processes occur in accordance with a rhythm regulated by the endogenous biological clock. This clock is programmed at the molecular level and synchronized with the daily light–dark cycle, as well as activities such as feeding, exercise, and social interactions. It consists of the core clock genes, Circadian Locomotor Output Cycles Protein Kaput (CLOCK) and Brain and Muscle Arnt-Like protein 1 (BMAL1), and their products, the period (PER) and cryptochrome (CRY) proteins, as well as an interlocked feedback loop which includes reverse-strand avian erythroblastic leukemia (ERBA) oncogene receptors (REV-ERBs) and retinoic acid-related orphan receptors (RORs). These genes are involved in the regulation of metabolic pathways and hormone release. Therefore, circadian rhythm disruption leads to development of metabolic syndrome (MetS). MetS refers to a cluster of risk factors (RFs), which are not only associated with the development of cardiovascular (CV) disease (CVD), but also with increased all-cause mortality. In this review, we consider the importance of the circadian rhythm in the regulation of metabolic processes, the significance of circadian misalignment in the pathogenesis of MetS, and the management of MetS in relation to the cellular molecular clock.
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Catalano, Federica, Francesca De Vito, Velia Cassano, Teresa Vanessa Fiorentino, Angela Sciacqua, and Marta Letizia Hribal. "Circadian Clock Desynchronization and Insulin Resistance." International Journal of Environmental Research and Public Health 20, no. 1 (December 20, 2022): 29. http://dx.doi.org/10.3390/ijerph20010029.
Full textAbstract:
The circadian rhythm regulates biological processes that occur within 24 h in living organisms. It plays a fundamental role in maintaining biological functions and responds to several inputs, including food intake, light/dark cycle, sleep/wake cycle, and physical activity. The circadian timing system comprises a central clock located in the suprachiasmatic nucleus (SCN) and tissue-specific clocks in peripheral tissues. Several studies show that the desynchronization of central and peripheral clocks is associated with an increased incidence of insulin resistance (IR) and related diseases. In this review, we discuss the current knowledge of molecular and cellular mechanisms underlying the impact of circadian clock dysregulation on insulin action. We focus our attention on two possible mediators of this interaction: the phosphatases belonging to the pleckstrin homology leucine-rich repeat protein phosphatase family (PHLPP) family and the deacetylase Sirtuin1. We believe that literature data, herein summarized, suggest that a thorough change of life habits, with the return to synchronized food intake, physical activity, and rest, would doubtless halt the vicious cycle linking IR to dysregulated circadian rhythms. However, since such a comprehensive change may be incompatible with the demand of modern society, clarifying the pathways involved may, nonetheless, contribute to the identification of therapeutic targets that may be exploited to cure or prevent IR-related diseases.