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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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Costello, Hannah M., and Michelle L. Gumz. "Circadian Rhythm, Clock Genes, and Hypertension: Recent Advances in Hypertension." Hypertension 78, no. 5 (November 2021): 1185–96. http://dx.doi.org/10.1161/hypertensionaha.121.14519.
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Accumulating evidence suggests that the molecular circadian clock is crucial in blood pressure (BP) control. Circadian rhythms are controlled by the central clock, which resides in the suprachiasmatic nucleus of the hypothalamus and peripheral clocks throughout the body. Both light and food cues entrain these clocks but whether these cues are important for the circadian rhythm of BP is a growing area of interest. The peripheral clocks in the smooth muscle, perivascular adipose tissue, liver, adrenal gland, and kidney have been recently implicated in the regulation of BP rhythm. Dysregulation of the circadian rhythm of BP is associated with adverse cardiorenal outcomes and increased risk of cardiovascular mortality. In this review, we summarize the most recent advances in peripheral clocks as BP regulators, highlight the adverse outcomes of disrupted circadian BP rhythm in hypertension, and provide insight into potential future work in areas exploring the circadian clock in BP control and chronotherapy. A better understanding of peripheral clock function in regulating the circadian rhythm of BP will help pave the way for targeted therapeutics in the treatment of circadian BP dysregulation and hypertension.
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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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Shakhmantsir, Iryna, and Amita Sehgal. "Splicing the Clock to Maintain and Entrain Circadian Rhythms." Journal of Biological Rhythms 34, no. 6 (August 7, 2019): 584–95. http://dx.doi.org/10.1177/0748730419868136.
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Circadian clocks drive daily rhythms of physiology and behavior in multiple organisms and synchronize these rhythms to environmental cycles of light and temperature. The basic mechanism of the clock consists of a transcription-translation feedback loop, in which key clock proteins negatively regulate their own transcription. Although much of the focus with respect to clock mechanisms has been on the regulation of transcription and on the stability and activity of clock proteins, it is clear that other regulatory processes also have to be involved to explain aspects of clock function. Here, we review the role of alternative splicing in circadian clocks. Starting with a discussion of the Drosophila clock and then extending to other major circadian model systems, we describe how the control of alternative splicing enables organisms to maintain their circadian clocks as well as to respond to environmental inputs, in particular to temperature changes.
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Myung, Jihwan, Mei-Yi Wu, Chun-Ya Lee, Amalia Ridla Rahim, Vuong Hung Truong, Dean Wu, Hugh David Piggins, and Mai-Szu Wu. "The Kidney Clock Contributes to Timekeeping by the Master Circadian Clock." International Journal of Molecular Sciences 20, no. 11 (June 5, 2019): 2765. http://dx.doi.org/10.3390/ijms20112765.
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The kidney harbors one of the strongest circadian clocks in the body. Kidney failure has long been known to cause circadian sleep disturbances. Using an adenine-induced model of chronic kidney disease (CKD) in mice, we probe the possibility that such sleep disturbances originate from aberrant circadian rhythms in kidney. Under the CKD condition, mice developed unstable behavioral circadian rhythms. When observed in isolation in vitro, the pacing of the master clock, the suprachiasmatic nucleus (SCN), remained uncompromised, while the kidney clock became a less robust circadian oscillator with a longer period. We find this analogous to the silencing of a strong slave clock in the brain, the choroid plexus, which alters the pacing of the SCN. We propose that the kidney also contributes to overall circadian timekeeping at the whole-body level, through bottom-up feedback in the hierarchical structure of the mammalian circadian clocks.
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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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Wu, Yiyang. "The Evolutionary Pathways of the Circadian Rhythms through Phylogenetical Analysis of Basal Circadian Genes." Highlights in Science, Engineering and Technology 54 (July 4, 2023): 367–76. http://dx.doi.org/10.54097/hset.v54i.9795.
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Circadian rhythm is the endogenous clock in organisms that regulates the performance of various physiological and metabolic events in accordance with the periodic oscillating changes in the environment, especially the periodic light-dark cycle. The clock has endowed organisms with the ability in anticipating environmental changes allowing them to adjust their survival strategies accordingly, promoting their selective fitness. However, the evolutionary path and the emergence of such an intricate and vital system remain elusive. The article aims to analyse the molecular architecture and components of the circadian clock among three kingdoms of plants, animals, fungi, and their unicellular ancestors, revealing the possible emergence of the circadian clock from the primordial circadian rhythm of prokaryotes to complicated rhythms seen in multicellular organisms. In comparative genetic analyses of the circadian clocks, researchers have identified homologs in the circadian genes of multicellular organisms with their unicellular ancestors, indicating prior emergence of the circadian clock than multicellularity. In addition, comparative genetic studies among fungi, animal, and plant circadian clocks implied that the emergence of circadian rhythms across the kingdoms resulted from convergent evolution due to the significant selective advantages concomitant with the circadian clock. Furthermore, the article also reviewed methods of gene transferring laterally, including horizontal gene transfer and endosymbiotic gene transfer, which may explain the overall similarities in the transcription-translation feedback mechanism among the many circadian rhythms. However, while genetic transfer among distantly related organisms enhanced biodiversity and biological innovations in nature, whether the horizontal changes of genetic materials contribute to the similar feedback loop of the circadian clock still requires further research to determine.
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Li, Meina, Lijun Cao, Musoki Mwimba, Yan Zhou, Ling Li, Mian Zhou, Patrick S. Schnable, Jamie A. O’Rourke, Xinnian Dong, and Wei Wang. "Comprehensive mapping of abiotic stress inputs into the soybean circadian clock." Proceedings of the National Academy of Sciences 116, no. 47 (November 1, 2019): 23840–49. http://dx.doi.org/10.1073/pnas.1708508116.
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The plant circadian clock evolved to increase fitness by synchronizing physiological processes with environmental oscillations. Crop fitness was artificially selected through domestication and breeding, and the circadian clock was identified by both natural and artificial selections as a key to improved fitness. Despite progress in Arabidopsis, our understanding of the crop circadian clock is still limited, impeding its rational improvement for enhanced fitness. To unveil the interactions between the crop circadian clock and various environmental cues, we comprehensively mapped abiotic stress inputs to the soybean circadian clock using a 2-module discovery pipeline. Using the “molecular timetable” method, we computationally surveyed publicly available abiotic stress-related soybean transcriptomes to identify stresses that have strong impacts on the global rhythm. These findings were then experimentally confirmed using a multiplexed RNA sequencing technology. Specific clock components modulated by each stress were further identified. This comprehensive mapping uncovered inputs to the plant circadian clock such as alkaline stress. Moreover, short-term iron deficiency targeted different clock components in soybean and Arabidopsis and thus had opposite effects on the clocks of these 2 species. Comparing soybean varieties with different iron uptake efficiencies suggests that phase modulation might be a mechanism to alleviate iron deficiency symptoms in soybean. These unique responses in soybean demonstrate the need to directly study crop circadian clocks. Our discovery pipeline may serve as a broadly applicable tool to facilitate these explorations.
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Bailey, Shannon M. "Emerging role of circadian clock disruption in alcohol-induced liver disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 315, no. 3 (September 1, 2018): G364—G373. http://dx.doi.org/10.1152/ajpgi.00010.2018.
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The detrimental health effects of excessive alcohol consumption are well documented. Alcohol-induced liver disease (ALD) is the leading cause of death from chronic alcohol use. As with many diseases, the etiology of ALD is influenced by how the liver responds to other secondary insults. The molecular circadian clock is an intrinsic cellular timing system that helps organisms adapt and synchronize metabolism to changes in their environment. The clock also influences how tissues respond to toxic, environmental, and metabolic stressors, like alcohol. Consistent with the essential role for clocks in maintaining health, genetic and environmental disruption of the circadian clock contributes to disease. While a large amount of rich literature is available showing that alcohol disrupts circadian-driven behaviors and that circadian clock disruption increases alcohol drinking and preference, very little is known about the role circadian clocks play in alcohol-induced tissue injuries. In this review, recent studies examining the effect alcohol has on the circadian clock in peripheral tissues (liver and intestine) and the impact circadian clock disruption has on development of ALD are presented. This review also highlights some of the rhythmic metabolic processes in the liver that are disrupted by alcohol and potential mechanisms through which alcohol disrupts the liver clock. Improved understanding of the mechanistic links between the circadian clock and alcohol will hopefully lead to the development of new therapeutic approaches for treating ALD and other alcohol-related organ pathologies.
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Helfrich-Förster, Charlotte, Michael N. Nitabach, and Todd C. Holmes. "Insect circadian clock outputs." Essays in Biochemistry 49 (June 30, 2011): 87–101. http://dx.doi.org/10.1042/bse0490087.
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Insects display an impressive variety of daily rhythms, which are most evident in their behaviour. Circadian timekeeping systems that generate these daily rhythms of physiology and behaviour all involve three interacting elements: the timekeeper itself (i.e. the clock), inputs to the clock through which it entrains and otherwise responds to environmental cues such as light and temperature, and outputs from the clock through which it imposes daily rhythms on various physiological and behavioural parameters. In insects, as in other animals, cellular clocks are embodied in clock neurons capable of sustained autonomous circadian rhythmicity, and those clock neurons are organized into clock circuits. Drosophila flies spend their entire lives in small areas near the ground, and use their circadian brain clock to regulate daily rhythms of rest and activity, so as to organize their behaviour appropriately to the daily rhythms of their local environment. Migratory locusts and butterflies, on the other hand, spend substantial portions of their lives high up in the air migrating long distances (sometimes thousands of miles) and use their circadian brain clocks to provide time-compensation to their sun-compass navigational systems. Interestingly, however, there appear to be substantial similarities in the cellular and network mechanisms that underlie circadian outputs in all insects.
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Richards, Jacob, and Michelle L. Gumz. "Mechanism of the circadian clock in physiology." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 304, no. 12 (June 15, 2013): R1053—R1064. http://dx.doi.org/10.1152/ajpregu.00066.2013.
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It has been well established that the circadian clock plays a crucial role in the regulation of almost every physiological process. It also plays a critical role in pathophysiological states including those of obesity and diabetes. Recent evidence has highlighted the potential for targeting the circadian clock as a potential drug target. New studies have also demonstrated the existence of “clock-independent effects” of the circadian proteins, leading to exciting new avenues of research in the circadian clock field in physiology. The goal of this review is to provide an introduction to and overview of the circadian clock in physiology, including mechanisms, targets, and role in disease states. The role of the circadian clocks in the regulation of the cardiovascular system, renal function, metabolism, the endocrine system, immune, and reproductive systems will be discussed.
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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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Amaral, Ian P. G., and Ian A. Johnston. "Circadian expression of clock and putative clock-controlled genes in skeletal muscle of the zebrafish." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 302, no. 1 (January 2012): R193—R206. http://dx.doi.org/10.1152/ajpregu.00367.2011.
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To identify circadian patterns of gene expression in skeletal muscle, adult male zebrafish were acclimated for 2 wk to a 12:12-h light-dark photoperiod and then exposed to continuous darkness for 86 h with ad libitum feeding. The increase in gut food content associated with the subjective light period was much diminished by the third cycle, enabling feeding and circadian rhythms to be distinguished. Expression of zebrafish paralogs of mammalian transcriptional activators of the circadian mechanism ( bmal1, clock1, and rora) followed a rhythmic pattern with a ∼24-h periodicity. Peak expression of rora paralogs occurred at the beginning of the subjective light period [Zeitgeber time (ZT)07 and ZT02 for roraa and rorab], whereas the highest expression of bmal1 and clock paralogs occurred 12 h later (ZT13–15 and ZT16 for bmal and clock paralogs). Expression of the transcriptional repressors cry1a, per1a/1b, per2, per3, nr1d2a/2b, and nr1d1 also followed a circadian pattern with peak expression at ZT0–02. Expression of the two paralogs of cry2 occurred in phase with clock1a/1b. Duplicated genes had a high correlation of expression except for paralogs of clock1, nr1d2, and per1, with cry1b showing no circadian pattern. The highest expression difference was 9.2-fold for the activator bmal1b and 51.7-fold for the repressor per1a. Out of 32 candidate clock-controlled genes, only myf6, igfbp3, igfbp5b, and hsf2 showed circadian expression patterns. Igfbp3, igfbp5b, and myf6 were expressed in phase with clock1a/1b and had an average of twofold change in expression from peak to trough, whereas hsf2 transcripts were expressed in phase with cry1a and had a 7.2-fold-change in expression. The changes in expression of clock and clock-controlled genes observed during continuous darkness were also observed at similar ZTs in fish exposed to a normal photoperiod in a separate control experiment. The role of circadian clocks in regulating muscle maintenance and growth are discussed.
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Manella, Gal, Rona Aviram, Nityanand Bolshette, Sapir Muvkadi, Marina Golik, David F. Smith, and Gad Asher. "Hypoxia induces a time- and tissue-specific response that elicits intertissue circadian clock misalignment." Proceedings of the National Academy of Sciences 117, no. 1 (December 17, 2019): 779–86. http://dx.doi.org/10.1073/pnas.1914112117.
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The occurrence and sequelae of disorders that lead to hypoxic spells such as asthma, chronic obstructive pulmonary disease, and obstructive sleep apnea (OSA) exhibit daily variance. This prompted us to examine the interaction between the hypoxic response and the circadian clock in vivo. We found that the global transcriptional response to acute hypoxia is tissue-specific and time-of-day–dependent. In particular, clock components differentially responded at the transcriptional and posttranscriptional level, and these responses depended on an intact circadian clock. Importantly, exposure to hypoxia phase-shifted clocks in a tissue-dependent manner led to intertissue circadian clock misalignment. This differential response relied on the intrinsic properties of each tissue and could be recapitulated ex vivo. Notably, circadian misalignment was also elicited by intermittent hypoxia, a widely used model for OSA. Given that phase coherence between circadian clocks is considered favorable, we propose that hypoxia leads to circadian misalignment, contributing to the pathophysiology of OSA and potentially other diseases that involve hypoxia.
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Harper, Ross E. F., Maite Ogueta, Peter Dayan, Ralf Stanewsky, and Joerg T. Albert. "Light Dominates Peripheral Circadian Oscillations in Drosophila melanogaster During Sensory Conflict." Journal of Biological Rhythms 32, no. 5 (September 13, 2017): 423–32. http://dx.doi.org/10.1177/0748730417724250.
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In Drosophila, as in other animals, the circadian clock is a singular entity in name and concept only. In reality, clock functions emerge from multiple processes and anatomical substrates. One distinction has conventionally been made between a central clock (in the brain) and peripheral clocks (e.g., in the gut and the eyes). Both types of clock generate robust circadian oscillations, which do not require external input. Furthermore, the phases of these oscillations remain exquisitely sensitive to specific environmental cues, such as the daily changes of light and temperature. When these cues conflict with one another, the central clock displays complex forms of sensory integration; how peripheral clocks respond to conflicting input is unclear. We therefore explored the effects of light and temperature misalignments on peripheral clocks. We show that under conflict, peripheral clocks preferentially synchronize to the light stimulus. This photic dominance requires the presence of the circadian photoreceptor, Cryptochrome.
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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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Young, Martin E. "Anticipating anticipation: pursuing identification of cardiomyocyte circadian clock function." Journal of Applied Physiology 107, no. 4 (October 2009): 1339–47. http://dx.doi.org/10.1152/japplphysiol.00473.2009.
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Diurnal rhythms in myocardial physiology (e.g., metabolism, contractile function) and pathophyiology (e.g., sudden cardiac death) are well establish and have classically been ascribed to time-of-day-dependent alterations in the neurohumoral milieu. Existence of an intramyocellular circadian clock has recently been exposed. Circadian clocks enable the cell to anticipate environmental stimuli, facilitating a timely and appropriate response. Generation of genetically modified mice with a targeted disruption of the cardiomyocyte circadian clock has provided an initial means for deciphering the functions of this transcriptionally based mechanism and allowed predictions regarding which environmental stimuli the heart anticipates (i.e., “anticipating anticipation”). Recent studies show that the cardiomyocyte circadian clock influences myocardial gene expression, β-adrenergic signaling, transcriptional responsiveness to fatty acids, triglyceride metabolism, heart rate, and cardiac output, as well as ischemia-reperfusion tolerance. In addition to reviewing current knowledge regarding the roles of the cardiomyocyte circadian clock, this article highlights putative frontiers in this field. The latter includes establishing molecular links between the cardiomyocyte circadian clock with identified functions, understanding the pathophysiological consequences of disruption of this mechanism, targeting resynchronization of the cardiomyocyte circadian clock for prevention/treatment of cardiovascular disease, linking the circadian clock with the cardiobeneficial effects of caloric restriction, and determining whether circadian clock genes are subject to epigenetic regulation. Information gained from studies investigating the cardiomyocyte circadian clock will likely translate to extracardiac tissues, such as skeletal muscle, liver, and adipose tissue.
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Lee, Kwangjun, Kwang-Seok Hong, Jonghoon Park, and Wonil Park. "Readjustment of circadian clocks by exercise intervention is a potential therapeutic target for sleep disorders: a narrative review." Physical Activity and Nutrition 28, no. 2 (June 30, 2024): 35–42. http://dx.doi.org/10.20463/pan.2024.0014.
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[Purpose] Circadian clocks are evolved endogenous biological systems that communicate with environmental cues to optimize physiological processes, such as the sleep-wake cycle, which is nearly related to quality of life. Sleep disorders can be treated using pharmacological strategies targeting melatonin, orexin, or core clock genes. Exercise has been widely explored as a behavioral treatment because it challenges homeostasis in the human body and affects the regulation of core clock genes. Exercise intervention at the appropriate time of the day can induce a phase shift in internal clocks. Although exercise is a strong external time cue for resetting the circadian clock, exercise therapy for sleep disorders remains poorly understood.[Methods] This review focused on exercise as a potential treatment for sleep disorders by tuning the internal circadian clock. We used scientific paper depositories, including Google Scholar, PubMed, and the Cochrane Library, to identify previous studies that investigated the effects of exercise on circadian clocks and sleep disorders.[Results] The exercise-induced adjustment of the circadian clock phase depended on exercise timing and individual chronotypes. Adjustment of circadian clocks through scheduled morning exercises can be appropriately prescribed for individuals with delayed sleep phase disorders. Individuals with advanced sleep phase disorders can synchronize their internal clocks with their living environment by performing evening exercises. Exercise-induced physiological responses are affected by age, sex, and current fitness conditions.[Conclusion] Personalized approaches are necessary when implementing exercise interventions for sleep disorders.
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Zhang, Haoran, Zengxuan Zhou, and Jinhu Guo. "The Function, Regulation, and Mechanism of Protein Turnover in Circadian Systems in Neurospora and Other Species." International Journal of Molecular Sciences 25, no. 5 (February 22, 2024): 2574. http://dx.doi.org/10.3390/ijms25052574.
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Circadian clocks drive a large array of physiological and behavioral activities. At the molecular level, circadian clocks are composed of positive and negative elements that form core oscillators generating the basic circadian rhythms. Over the course of the circadian period, circadian negative proteins undergo progressive hyperphosphorylation and eventually degrade, and their stability is finely controlled by complex post-translational pathways, including protein modifications, genetic codon preference, protein–protein interactions, chaperon-dependent conformation maintenance, degradation, etc. The effects of phosphorylation on the stability of circadian clock proteins are crucial for precisely determining protein function and turnover, and it has been proposed that the phosphorylation of core circadian clock proteins is tightly correlated with the circadian period. Nonetheless, recent studies have challenged this view. In this review, we summarize the research progress regarding the function, regulation, and mechanism of protein stability in the circadian clock systems of multiple model organisms, with an emphasis on Neurospora crassa, in which circadian mechanisms have been extensively investigated. Elucidation of the highly complex and dynamic regulation of protein stability in circadian clock networks would greatly benefit the integrated understanding of the function, regulation, and mechanism of protein stability in a wide spectrum of other biological processes.
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Challet, Etienne. "The circadian control of eating." Journal of Behavior and Feeding 1, no. 1 (July 1, 2021): 39–50. http://dx.doi.org/10.32870/jbf.v1i1.14.
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Eating is a complex behavior that is primarily governed by energy homeostasis and modulated by hedonic cues. Eating is also structured in time, due to circadian clocks that control its daily rhythmicity. These circadian clocks are organized into a network of several oscillating structures, including a master clock in the suprachiasmatic nuclei of the hypothalamus and several secondary clocks in the brain and peripheral organs. The light-entrainable master clock is a conductor for the secondary clocks via neuroendocrine signals. In contrast to the master clock, most secondary clocks are sensitive to the synchronizing effect of meal time. Besides controlling the daily feeding/fasting cycle, several coupled secondary clocks in the brain defining a so-called “food clock” also adjust the timing of meal anticipation, a rhythmic behavior that mammals exhibit right before scheduled feeding time. There are reciprocal interactions between energy metabolism and circadian rhythmicity. On the one hand, metabolic alterations, like obesity and type 2 diabetes, are frequently associated with circadian disturbances. On the other hand, circadian disturbances have deleterious effects on metabolic health. Feeding cues, such as meal timing, nature of the diet and quantity of ingested food, are strongly involved in these circadian disturbances. For instance, eating many calories at the “wrong” phase of the living cycle (e.g., at night for humans or during daytime in nocturnal animals) has obesogenic consequences. Besides management of total energy intake and expenditure, experimental evidence is given to show that daily timing of calorie intake, duration of eating window, together with a long enough nocturnal fasting are newly identified actors of energy balance. Accordingly, new nutritional strategies should be developed based on personalized chrononutrition.
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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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Patel, Sonal A., and Roman V. Kondratov. "Clock at the Core of Cancer Development." Biology 10, no. 2 (February 14, 2021): 150. http://dx.doi.org/10.3390/biology10020150.
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To synchronize various biological processes with the day and night cycle, most organisms have developed circadian clocks. This evolutionarily conserved system is important in the temporal regulation of behavior, physiology and metabolism. Multiple pathological changes associated with circadian disruption support the importance of the clocks in mammals. Emerging links have revealed interplay between circadian clocks and signaling networks in cancer. Understanding the cross-talk between the circadian clock and tumorigenesis is imperative for its prevention, management and development of effective treatment options. In this review, we summarize the role of the circadian clock in regulation of one important metabolic pathway, insulin/IGF1/PI3K/mTOR signaling, and how dysregulation of this metabolic pathway could lead to uncontrolled cancer cell proliferation and growth. Targeting the circadian clock and rhythms either with recently discovered pharmaceutical agents or through environmental cues is a new direction in cancer chronotherapy. Combining the circadian approach with traditional methods, such as radiation, chemotherapy or the recently developed, immunotherapy, may improve tumor response, while simultaneously minimizing the adverse effects commonly associated with cancer therapies.
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Charoensuksai, Purin, and Wei Xu. "PPARs in Rhythmic Metabolic Regulation and Implications in Health and Disease." PPAR Research 2010 (2010): 1–9. http://dx.doi.org/10.1155/2010/243643.
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The circadian rhythm, controlled by a complex network of cellular transcription factors, orchestrates behavior and physiology in the vast majority of animals. The circadian system is comprised of a master clock located in central nervous system with 24-hour rotation and periphery clocks to ensure optimal timing of physiology in peripheral tissues. Circadian expression of peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor superfamily and key mediators of energy homeostasis and metabolism, is regulated by clock genes. PPARs serve as sensors of nutrient and energy/metabolism status to temporally entrain peripheral clock. Metabolism and circadian clocks are tightly intertwined: clock genes drive metabolism, and various metabolic parameters affect clock genes, producing a reciprocal feedback relationship. Due to PPARs' robust relationship with energy status and metabolism, the aberration of PPARs in the biological clock system leads to abnormal expression of genes in metabolic pathways, thus, contributing to etiology of metabolic syndrome. Studying PPARs' functions under the context of the mammalian circadian system could advance our understanding of how energy and metabolic status are maintained in the body, which may ultimately lead to rhythmic medical treatment against metabolic syndrome.
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Wang, Xingwei, Yanfei Hu, and Wei Wang. "Comparative Analysis of Circadian Transcriptomes Reveals Circadian Characteristics between Arabidopsis and Soybean." Plants 12, no. 19 (September 22, 2023): 3344. http://dx.doi.org/10.3390/plants12193344.
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The circadian clock, an endogenous timing system, exists in nearly all organisms on Earth. The plant circadian clock has been found to be intricately linked with various essential biological activities. Extensive studies of the plant circadian clock have yielded valuable applications. However, the distinctions of circadian clocks in two important plant species, Arabidopsis thaliana and Glycine max (soybean), remain largely unexplored. This study endeavors to address this gap by conducting a comprehensive comparison of the circadian transcriptome profiles of Arabidopsis and soybean to uncover their distinct circadian characteristics. Utilizing non-linear regression fitting (COS) integrated with weights, we identified circadian rhythmic genes within both organisms. Through an in-depth exploration of circadian parameters, we unveiled notable differences between Arabidopsis and soybean. Furthermore, our analysis of core circadian clock genes shed light on the distinctions in central oscillators between these two species. Additionally, we observed that the homologous genes of Arabidopsis circadian clock genes in soybean exert a significant influence on the regulation of flowering and maturity of soybean. This phenomenon appears to stem from shifts in circadian parameters within soybean genes. These findings highlight contrasting biological activities under circadian regulation in Arabidopsis and soybean. This study not only underscores the distinctive attributes of these species, but also offers valuable insights for further scrutiny into the soybean circadian clock and its potential applications.
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Margay, Adil Rahim, Suhail Ashraf, Nusrat Fatimah, Saliah Gul Jabeen, Mansoor Showkat, Krishna Nayana R U, Sampatirao Dilip, Sudhakar Reddy Basu, and K. A. Aswathy. "Plant Circadian Clocks: Unravelling the Molecular Rhythms of Nature." International Journal of Plant & Soil Science 36, no. 8 (August 6, 2024): 596–617. http://dx.doi.org/10.9734/ijpss/2024/v36i84890.
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The circadian clock is a fundamental biological mechanism that allows organisms to synchronize their internal processes with the external environment, thereby optimizing growth, development, and physiology. In plants, circadian rhythms govern various aspects of their life cycle, including germination, leaf movement, flowering, and responses to environmental cues such as light and temperature. Understanding the molecular mechanisms underlying plant circadian clocks is essential not only for elucidating fundamental principles of plant biology but also for applications in agriculture and biotechnology. This review delves into the intricate molecular networks that comprise plant circadian clocks, focusing on key components and their interactions. At the core of these clocks are transcription-translation feedback loops (TTFLs) involving a set of clock genes. The central oscillator, composed of genes such as CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), LATE ELONGATED HYPOCOTYL (LHY), TIMING OF CAB EXPRESSION 1 (TOC1), and PSEUDO-RESPONSE REGULATOR (PRR) genes, drives rhythmic expression of downstream clock-controlled genes (CCGs). The interplay between positive and negative regulators within the TTFLs generates robust oscillations with a period of approximately 24 hours. Additionally, post-translational modifications, protein-protein interactions, and chromatin remodeling contribute to fine-tuning the circadian system, allowing plants to adapt to changing environmental conditions. Light perception through photoreceptors such as phytochromes and cryptochromes plays a crucial role in entraining the circadian clock to external cues, ensuring synchronization with the day-night cycle. Furthermore, recent advancements in omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have provided unprecedented insights into the complexity and plasticity of plant circadian clocks. Integration of multi-omics data has facilitated the construction of comprehensive regulatory networks and computational models, enabling predictive understanding of clock function and behavior under diverse conditions. Overall, unraveling the molecular rhythms of plant circadian clocks not only enhances our knowledge of fundamental biological processes but also holds promise for improving crop productivity, stress resilience, and sustainability in agriculture through targeted manipulation of clock components and their associated pathways. Future research endeavors will undoubtedly continue to unveil the intricacies of these fascinating timekeeping mechanisms, further enriching our understanding of the molecular rhythms of nature.
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Hirose, Misa, Alexei Leliavski, Leonardo Vinícius Monteiro de Assis, Olga Matveeva, Ludmila Skrum, Werner Solbach, Henrik Oster, and Isabel Heyde. "Chronic Inflammation Disrupts Circadian Rhythms in Splenic CD4+ and CD8+ T Cells in Mice." Cells 13, no. 2 (January 13, 2024): 151. http://dx.doi.org/10.3390/cells13020151.
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Internal circadian clocks coordinate 24 h rhythms in behavior and physiology. Many immune functions show daily oscillations, and cellular circadian clocks can impact immune functions and disease outcome. Inflammation may disrupt circadian clocks in peripheral tissues and innate immune cells. However, it remains elusive if chronic inflammation impacts adaptive immune cell clock, e.g., in CD4+ and CD8+ T lymphocytes. We studied this in the experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis, as an established experimental paradigm for chronic inflammation. We analyzed splenic T cell circadian clock and immune gene expression rhythms in mice with late-stage EAE, CFA/PTx-treated, and untreated mice. In both treatment groups, clock gene expression rhythms were altered with differential effects for baseline expression and peak phase compared with control mice. Most immune cell marker genes tested in this study did not show circadian oscillations in either of the three groups, but time-of-day- independent alterations were observed in EAE and CFA/PTx compared to control mice. Notably, T cell effects were likely independent of central clock function as circadian behavioral rhythms in EAE mice remained intact. Together, chronic inflammation induced by CFA/PTx treatment and EAE immunization has lasting effects on circadian rhythms in peripheral immune cells.
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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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Yari Kamrani, Yousef, Aida Shomali, Sasan Aliniaeifard, Oksana Lastochkina, Moein Moosavi-Nezhad, Nima Hajinajaf, and Urszula Talar. "Regulatory Role of Circadian Clocks on ABA Production and Signaling, Stomatal Responses, and Water-Use Efficiency under Water-Deficit Conditions." Cells 11, no. 7 (March 29, 2022): 1154. http://dx.doi.org/10.3390/cells11071154.
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Plants deploy molecular, physiological, and anatomical adaptations to cope with long-term water-deficit exposure, and some of these processes are controlled by circadian clocks. Circadian clocks are endogenous timekeepers that autonomously modulate biological systems over the course of the day–night cycle. Plants’ responses to water deficiency vary with the time of the day. Opening and closing of stomata, which control water loss from plants, have diurnal responses based on the humidity level in the rhizosphere and the air surrounding the leaves. Abscisic acid (ABA), the main phytohormone modulating the stomatal response to water availability, is regulated by circadian clocks. The molecular mechanism of the plant’s circadian clock for regulating stress responses is composed not only of transcriptional but also posttranscriptional regulatory networks. Despite the importance of regulatory impact of circadian clock systems on ABA production and signaling, which is reflected in stomatal responses and as a consequence influences the drought tolerance response of the plants, the interrelationship between circadian clock, ABA homeostasis, and signaling and water-deficit responses has to date not been clearly described. In this review, we hypothesized that the circadian clock through ABA directs plants to modulate their responses and feedback mechanisms to ensure survival and to enhance their fitness under drought conditions. Different regulatory pathways and challenges in circadian-based rhythms and the possible adaptive advantage through them are also discussed.
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Beaulé, Christian, and Hai-Ying M. Cheng. "The Acetyltransferase CLOCK Is Dispensable for Circadian Aftereffects in Mice." Journal of Biological Rhythms 26, no. 6 (November 30, 2011): 561–64. http://dx.doi.org/10.1177/0748730411416329.
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Recent demonstration of the histone acetyltransferase activity of the Clock gene greatly expanded the regulatory role of circadian clocks in gene transcription. Clock and its partner Bmal1 are responsible for the generation of circadian oscillations that are synchronized (entrained) to the external light cycle. Entraining light often produces long-lasting changes in the endogenous period called aftereffects. Aftereffects are light-dependent alterations in the speed of free-running rhythms that persist for several weeks upon termination of light exposure. How light causes such long-lasting changes is unknown. However, the persistent nature of circadian aftereffects in conjunction with the long-term effects of epigenetic modifications on development and various aspects of brain physiology prompted us to hypothesize that the histone acetyltransferase CLOCK was required for circadian aftereffects. The authors exposed Clock knockout mice to 25-hour light cycles and report that these mice retain the ability to display circadian aftereffects, indicating that Clock is dispensable for this form of circadian plasticity.
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James, Allan B., José A. Monreal, Gillian A. Nimmo, Ciarán L. Kelly, Pawel Herzyk, Gareth I. Jenkins, and Hugh G. Nimmo. "The Circadian Clock inArabidopsisRoots Is a Simplified Slave Version of the Clock in Shoots." Science 322, no. 5909 (December 19, 2008): 1832–35. http://dx.doi.org/10.1126/science.1161403.
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The circadian oscillator in eukaryotes consists of several interlocking feedback loops through which the expression of clock genes is controlled. It is generally assumed that all plant cells contain essentially identical and cell-autonomous multiloop clocks. Here, we show that the circadian clock in the roots of matureArabidopsisplants differs markedly from that in the shoots and that the root clock is synchronized by a photosynthesis-related signal from the shoot. Two of the feedback loops of the plant circadian clock are disengaged in roots, because two key clock components, the transcription factors CCA1 and LHY, are able to inhibit gene expression in shoots but not in roots. Thus, the plant clock is organ-specific but not organ-autonomous.
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Eelderink-Chen, Zheng, Gabriella Mazzotta, Marcel Sturre, Jasper Bosman, Till Roenneberg, and Martha Merrow. "A circadian clock in Saccharomyces cerevisiae." Proceedings of the National Academy of Sciences 107, no. 5 (January 19, 2010): 2043–47. http://dx.doi.org/10.1073/pnas.0907902107.
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Circadian timing is a fundamental biological process, underlying cellular physiology in animals, plants, fungi, and cyanobacteria. Circadian clocks organize gene expression, metabolism, and behavior such that they occur at specific times of day. The biological clocks that orchestrate these daily changes confer a survival advantage and dominate daily behavior, for example, waking us in the morning and helping us to sleep at night. The molecular mechanism of circadian clocks has been sketched out in genetic model systems from prokaryotes to humans, revealing a combination of transcriptional and posttranscriptional pathways, but the clock mechanism is far from solved. Although Saccharomyces cerevisiae is among the most powerful genetic experimental systems and, as such, could greatly contribute to our understanding of cellular timing, it still remains absent from the repertoire of circadian model organisms. Here, we use continuous cultures of yeast, establishing conditions that reveal characteristic clock properties similar to those described in other species. Our results show that metabolism in yeast shows systematic circadian entrainment, responding to cycle length and zeitgeber (stimulus) strength, and a (heavily damped) free running rhythm. Furthermore, the clock is obvious in a standard, haploid, auxotrophic strain, opening the door for rapid progress into cellular clock mechanisms.
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Ma, Qianwen, Genlin Mo, and Yong Tan. "Micro RNAs and the biological clock: a target for diseases associated with a loss of circadian regulation." African Health Sciences 20, no. 4 (December 16, 2020): 1887–94. http://dx.doi.org/10.4314/ahs.v20i4.46.
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Background: Circadian clocks are self-sustaining oscillators that coordinate behavior and physiology over a 24 hour peri- od, achieving time-dependent homeostasis with the external environment. The molecular clocks driving circadian rhythmic changes are based on intertwined transcriptional/translational feedback loops that combine with a range of environmental and metabolic stimuli to generate daily internal programing. Understanding how biological rhythms are generated through- out the body and the reasons for their dysregulation can provide avenues for temporally directed therapeutics. Summary: In recent years, microRNAs have been shown to play important roles in the regulation of the circadian clock, particularly in Drosophila, but also in some small animal and human studies. This review will summarize our current un- derstanding of the role of miRNAs during clock regulation, with a particular focus on the control of clock regulated gene expression.
 Keywords: MicroRNAs; biological clock; circadian rhythm.
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Vlachou, Denise, Maria Veretennikova, Laura Usselmann, Vadim Vasilyev, Sascha Ott, Georg A. Bjarnason, Robert Dallmann, Francis Levi, and David A. Rand. "TimeTeller: A tool to probe the circadian clock as a multigene dynamical system." PLOS Computational Biology 20, no. 2 (February 29, 2024): e1011779. http://dx.doi.org/10.1371/journal.pcbi.1011779.
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Recent studies have established that the circadian clock influences onset, progression and therapeutic outcomes in a number of diseases including cancer and heart diseases. Therefore, there is a need for tools to measure the functional state of the molecular circadian clock and its downstream targets in patients. Moreover, the clock is a multi-dimensional stochastic oscillator and there are few tools for analysing it as a noisy multigene dynamical system. In this paper we consider the methodology behind TimeTeller, a machine learning tool that analyses the clock as a noisy multigene dynamical system and aims to estimate circadian clock function from a single transcriptome by modelling the multi-dimensional state of the clock. We demonstrate its potential for clock systems assessment by applying it to mouse, baboon and human microarray and RNA-seq data and show how to visualise and quantify the global structure of the clock, quantitatively stratify individual transcriptomic samples by clock dysfunction and globally compare clocks across individuals, conditions and tissues thus highlighting its potential relevance for advancing circadian medicine.
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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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Cruz, Leo Nava Piorsky Dominici, Rayane Teles-de-Freitas, Maria Eduarda Barreto Resck, Andresa Borges de Araujo Fonseca, Karine Pedreira Padilha, Luana Cristina Farnesi, Luciana Ordunha Araripe, and Rafaela Vieira Bruno. "Light and dark cycles modify the expression of clock genes in the ovaries of Aedes aegypti in a noncircadian manner." PLOS ONE 18, no. 10 (October 19, 2023): e0287237. http://dx.doi.org/10.1371/journal.pone.0287237.
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Circadian oscillators (i.e., circadian clocks) are essential to producing the circadian rhythms observed in virtually all multicellular organisms. In arthropods, many rhythmic behaviors are generated by oscillations of the central pacemaker, specific groups of neurons of the protocerebrum in which the circadian oscillator molecular machinery is expressed and works; however, oscillators located in other tissues (i.e., peripheral clocks) could also contribute to certain rhythms, but are not well known in non-model organisms. Here, we investigated whether eight clock genes that likely constitute the Aedes aegypti clock are expressed in a circadian manner in the previtellogenic ovaries of this mosquito. Also, we asked if insemination by conspecific males would alter the expression profiles of these clock genes. We observed that the clock genes do not have a rhythmic expression profile in the ovaries of virgin (VF) or inseminated (IF) females, except for period, which showed a rhythmic expression profile in ovaries of IF kept in light and dark (LD) cycles, but not in constant darkness (DD). The mean expression of seven clock genes was affected by the insemination status (VF or IF) or the light condition (LD 12:12 or DD), among which five were affected solely by the light condition, one solely by the insemination status, and one by both factors. Our results suggest that a functional circadian clock is absent in the ovaries of A. aegypti. Still, their differential mean expression promoted by light conditions or insemination suggests roles other than circadian rhythms in this mosquito’s ovaries.
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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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Froy, Oren. "The circadian clock and metabolism." Clinical Science 120, no. 2 (October 8, 2010): 65–72. http://dx.doi.org/10.1042/cs20100327.
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Mammals have developed an endogenous circadian clock located in the SCN (suprachiasmatic nuclei) of the anterior hypothalamus that responds to the environmental light–dark cycle. Human homoeostatic systems have adapted to daily changes in a way that the body anticipates the sleep and activity periods. Similar clocks have been found in peripheral tissues, such as the liver, intestine and adipose tissue. Recently it has been found that the circadian clock regulates cellular and physiological functions in addition to the expression and/or activity of enzymes and hormones involved in metabolism. In turn, key metabolic enzymes and transcription activators interact with and affect the core clock mechanism. Animals with mutations in clock genes that disrupt cellular rhythmicity have provided evidence to the relationship between the circadian clock and metabolic homoeostasis. The present review will summarize recent findings concerning the relationship between metabolism and circadian rhythms.
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de Assis, Leonardo Vinícius Monteiro, and Henrik Oster. "The circadian clock and metabolic homeostasis: entangled networks." Cellular and Molecular Life Sciences 78, no. 10 (March 8, 2021): 4563–87. http://dx.doi.org/10.1007/s00018-021-03800-2.
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AbstractThe circadian clock exerts an important role in systemic homeostasis as it acts a keeper of time for the organism. The synchrony between the daily challenges imposed by the environment needs to be aligned with biological processes and with the internal circadian clock. In this review, it is provided an in-depth view of the molecular functioning of the circadian molecular clock, how this system is organized, and how central and peripheral clocks communicate with each other. In this sense, we provide an overview of the neuro-hormonal factors controlled by the central clock and how they affect peripheral tissues. We also evaluate signals released by peripheral organs and their effects in the central clock and other brain areas. Additionally, we evaluate a possible communication between peripheral tissues as a novel layer of circadian organization by reviewing recent studies in the literature. In the last section, we analyze how the circadian clock can modulate intracellular and tissue-dependent processes of metabolic organs. Taken altogether, the goal of this review is to provide a systemic and integrative view of the molecular clock function and organization with an emphasis in metabolic tissues.
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Fletcher, Elizabeth K., Monica Kanki, James Morgan, David W. Ray, Lea M. Delbridge, Peter J. Fuller, Colin D. Clyne, and Morag J. Young. "Cardiomyocyte transcription is controlled by combined mineralocorticoid receptor and circadian clock signalling." Journal of Endocrinology 241, no. 1 (April 2019): 17–29. http://dx.doi.org/10.1530/joe-18-0584.
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We previously identified a critical pathogenic role for mineralocorticoid receptor (MR) activation in cardiomyocytes that included a potential interaction between the MR and the molecular circadian clock. While glucocorticoid regulation of the circadian clock is undisputed, studies on MR interactions with circadian clock signalling are limited. We hypothesised that the MR influences cardiac circadian clock signalling, and vice versa. Aldosterone or corticosterone (10 nM) regulated Cry1, Per1, Per2 and ReverbA (Nr1d1) gene expression patterns in H9c2 cells over 24 h. MR-dependent regulation of circadian gene promoters containing GREs and E-box sequences was established for CLOCK, Bmal, CRY1 and CRY2, PER1 and PER2 and transcriptional activators CLOCK and Bmal modulated MR-dependent transcription of a subset of these promoters. We also demonstrated differential regulation of MR target gene expression in hearts of mice 4 h after administration of aldosterone at 08:00 h vs 20:00 h. Our data support MR regulation of a subset of circadian genes, with endogenous circadian transcription factors CLOCK and BMAL modulating the response. This unsuspected relationship links MR in the heart to circadian rhythmicity at the molecular level and has important implications for the biology of MR signalling in response to aldosterone as well as cortisol. These data are consistent with MR signalling in the brain where, like the heart, it preferentially responds to cortisol. Given the undisputed requirement for diurnal cortisol release in the entrainment of peripheral clocks, the present study highlights the MR as an important mechanism for transducing the circadian actions of cortisol in addition to glucocorticoid receptor (GR) in the heart.
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McWatters, Harriet G., Laura C. Roden, and Dorothee Staiger. "Picking out parallels: plant circadian clocks in context." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, no. 1415 (November 29, 2001): 1735–43. http://dx.doi.org/10.1098/rstb.2001.0936.
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Molecular models have been described for the circadian clocks of representatives of several different taxa. Much of the work on the plant circadian system has been carried out using the thale cress, Arabidopsis thaliana , as a model. We discuss the roles of genes implicated in the plant circadian system, with special emphasis on Arabidopsis . Plants have an endogenous clock that regulates many aspects of circadian and photoperiodic behaviour. Despite the discovery of components that resemble those involved in the clocks of animals or fungi, no coherent model of the plant clock has yet been proposed. In this review, we aim to provide an overview of studies of the Arabidopsis circadian system. We shall compare these with results from different taxa and discuss them in the context of what is known about clocks in other organisms.
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Sharma, Ashish, Gautam Sethi, Murtaza M. Tambuwala, Alaa A. A. Aljabali, Dinesh Kumar Chellappan, Kamal Dua, and Rohit Goyal. "Circadian Rhythm Disruption and Alzheimer’s Disease: The Dynamics of a Vicious Cycle." Current Neuropharmacology 19, no. 2 (December 31, 2020): 248–64. http://dx.doi.org/10.2174/1570159x18666200429013041.
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: All mammalian cells exhibit circadian rhythm in cellular metabolism and energetics. Autonomous cellular clocks are modulated by various pathways that are essential for robust time keeping. In addition to the canonical transcriptional translational feedback loop, several new pathways of circadian timekeeping - non-transcriptional oscillations, post-translational modifications, epigenetics and cellular signaling in the circadian clock - have been identified. The physiology of circadian rhythm is expansive, and its link to the neurodegeneration is multifactorial. Circadian rhythm disruption is prevelant in contamporary society where light-noise, shift-work, and transmeridian travel are commonplace, and is also reported from the early stages of Alzheimer's disease (AD). Circadian alignment by bright light therapy in conjunction with chronobiotics is beneficial for treating sundowning syndrome and other cognitive symptoms in advanced AD patients. We performed a comprehensive analysis of the clinical and translational reports to review the physiology of the circadian clock, delineate its dysfunction in AD, and unravel the dynamics of the vicious cycle between two pathologies. The review delineates the role of putative targets like clock proteins PER, CLOCK, BMAL1, ROR, and clock-controlled proteins like AVP, SIRT1, FOXO, and PK2 towards future approaches for management of AD. Furthermore, the role of circadian rhythm disruption in aging is delineated.
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Oosterman, Johanneke E., Andries Kalsbeek, Susanne E. la Fleur, and Denise D. Belsham. "Impact of nutrients on circadian rhythmicity." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 308, no. 5 (March 1, 2015): R337—R350. http://dx.doi.org/10.1152/ajpregu.00322.2014.
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The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to the environment by light, peripheral clocks are entrained by various factors, of which feeding/fasting is the most important. Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and Type 2 diabetes. Diets high in fat or sugar have been shown to alter circadian clock function. This review discusses the recent findings concerning the influence of nutrients, in particular fatty acids and glucose, on behavioral and molecular circadian rhythms and will summarize critical studies describing putative mechanisms by which these nutrients are able to alter normal circadian rhythmicity, in the SCN, in non-SCN brain areas, as well as in peripheral organs. As the effects of fat and sugar on the clock could be through alterations in energy status, the role of specific nutrient sensors will be outlined, as well as the molecular studies linking these components to metabolism. Understanding the impact of specific macronutrients on the circadian clock will allow for guidance toward the composition and timing of meals optimal for physiological health, as well as putative therapeutic targets to regulate the molecular clock.
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Erisa, Kungu. "Immunomodulation through the Circadian Clock: Impacts on Inflammation and Immunity." NEWPORT INTERNATIONAL JOURNAL OF PUBLIC HEALTH AND PHARMACY 5, no. 3 (November 20, 2024): 43–47. http://dx.doi.org/10.59298/nijpp/2024/5343470.
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The circadian clock, an intrinsic timekeeping system regulating physiological functions over a 24-hour cycle, profoundly influences immune responses and inflammation. Immune cells, including neutrophils, macrophages, and lymphocytes, exhibit circadian rhythms in their numbers, function, and migration. These rhythms are regulated by both central and peripheral clocks, synchronizing immune cell activity with environmental cues. The circadian clock modulates key immune processes such as leukocyte trafficking, cytokine production, and phagocytosis, affecting the body’s ability to respond to pathogens and tissue injury. Furthermore, circadian rhythms tightly control inflammatory pathways, including NF-κB signaling, and regulate the balance between pro- and anti-inflammatory states in macrophages. Disruptions to circadian rhythms—due to factors like shift work or sleep disorders—are associated with heightened inflammation and increased risk for inflammatory diseases, such as autoimmune disorders, metabolic syndromes, and cancer. Understanding how circadian rhythms govern immune functions has significant implications for chronotherapy, which aims to optimize the timing of treatments to improve efficacy and reduce adverse effects. This review explores the mechanisms through which the circadian clock modulates immune responses and inflammation, highlighting the potential for circadian-based therapies in managing inflammatory and immune-related diseases. Keywords: Circadian clock, immunity, inflammation, immune cells, chronotherapy.
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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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An, Zheming, Benedetto Piccoli, Martha Merrow, and Kwangwon Lee. "A Unified Model for Entrainment by Circadian Clocks: Dynamic Circadian Integrated Response Characteristic (dCiRC)." Journal of Biological Rhythms 37, no. 2 (February 13, 2022): 202–15. http://dx.doi.org/10.1177/07487304211069454.
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Circadian rhythms are ubiquitous and are observed in all biological kingdoms. In nature, their primary characteristic or phenotype is the phase of entrainment. There are two main hypotheses related to how circadian clocks entrain, parametric and non-parametric models. The parametric model focuses on the gradual changes of the clock parameters in response to the changing ambient condition, whereas the non-parametric model focuses on the instantaneous change of the phase of the clock in response to the zeitgeber. There are ample empirical data supporting both models. However, only recently has a unifying model been proposed, the circadian integrated response characteristic (CiRC). In the current study, we developed a system of ordinary differential equations, dynamic CiRC (dCiRC), that describes parameters of circadian rhythms and predicts the phase of entrainment in zeitgeber cycles. dCiRC mathematically extracts the underlying information of velocity changes of the internal clock that reflects the parametric model and the phase shift trajectory that reflects the non-parametric model from phase data under entraining conditions. As a proof of concept, we measured clock parameters of 26 Neurospora crassa ecotypes in both cycling and constant conditions using dCiRC. Our data showed that the morning light shortens the period of the clock while the afternoon light lengthens it. We also found that individual ecotypes have different strategies of integrating light effects to accomplish the optimal phase of entrainment, a model feature that is consistent with our knowledge of how circadian clocks are organized and encoded. The unified model dCiRC will provide new insights into how circadian clocks function under different zeitgeber conditions. We suggest that this type of model may be useful in the advent of chronotherapies.
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Uehara, Takahiro N., Yoshiyuki Mizutani, Keiko Kuwata, Tsuyoshi Hirota, Ayato Sato, Junya Mizoi, Saori Takao, et al. "Casein kinase 1 family regulates PRR5 and TOC1 in the Arabidopsis circadian clock." Proceedings of the National Academy of Sciences 116, no. 23 (May 16, 2019): 11528–36. http://dx.doi.org/10.1073/pnas.1903357116.
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The circadian clock provides organisms with the ability to adapt to daily and seasonal cycles. Eukaryotic clocks mostly rely on lineage-specific transcriptional-translational feedback loops (TTFLs). Posttranslational modifications are also crucial for clock functions in fungi and animals, but the posttranslational modifications that affect the plant clock are less understood. Here, using chemical biology strategies, we show that the Arabidopsis CASEIN KINASE 1 LIKE (CKL) family is involved in posttranslational modification in the plant clock. Chemical screening demonstrated that an animal CDC7/CDK9 inhibitor, PHA767491, lengthens the Arabidopsis circadian period. Affinity proteomics using a chemical probe revealed that PHA767491 binds to and inhibits multiple CKL proteins, rather than CDC7/CDK9 homologs. Simultaneous knockdown of Arabidopsis CKL-encoding genes lengthened the circadian period. CKL4 phosphorylated transcriptional repressors PSEUDO-RESPONSE REGULATOR 5 (PRR5) and TIMING OF CAB EXPRESSION 1 (TOC1) in the TTFL. PHA767491 treatment resulted in accumulation of PRR5 and TOC1, accompanied by decreasing expression of PRR5- and TOC1-target genes. A prr5 toc1 double mutant was hyposensitive to PHA767491-induced period lengthening. Together, our results reveal posttranslational modification of transcriptional repressors in plant clock TTFL by CK1 family proteins, which also modulate nonplant circadian clocks.
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Johnson, C. H., Y. Nakaoka, and I. Miwa. "The effects of altering extracellular potassium ion concentration on the membrane potential and circadian clock of Paramecium bursaria." Journal of Experimental Biology 197, no. 1 (December 1, 1994): 295–308. http://dx.doi.org/10.1242/jeb.197.1.295.
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In some neural models of circadian rhythmicity, membrane potential and transmembrane flux of potassium and calcium ions appear to play important roles in the entrainment and central mechanisms of the biological clock. We wondered whether these cellular variables might be generally involved in circadian clocks, even non-neural clocks. Therefore, we tested the impact of changing extracellular potassium level on the circadian rhythm of photoaccumulation of Paramecium cells, whose membrane potential responds to changes of extracellular potassium in a manner similar to that of neurones. We found that pulse or step changes of extracellular potassium concentration did not phase-shift the circadian clock of P. bursaria cells in a phase-specific manner. Furthermore, modifying the extracellular concentration of calcium did not affect the magnitude of light-induced phase resetting. Therefore, while membrane potential and calcium fluxes may be crucial components of the circadian clock system in some organisms, especially in neural systems that involve intercellular communication, the P. bursaria data indicate that membrane potential changes are not necessarily an intrinsic component of circadian organization at the cellular level.
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Ahmad, Myra, Wanhe Li, and Deniz Top. "Integration of Circadian Clock Information in the Drosophila Circadian Neuronal Network." Journal of Biological Rhythms 36, no. 3 (March 1, 2021): 203–20. http://dx.doi.org/10.1177/0748730421993953.
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Circadian clocks are biochemical time-keeping machines that synchronize animal behavior and physiology with planetary rhythms. In Drosophila, the core components of the clock comprise a transcription/translation feedback loop and are expressed in seven neuronal clusters in the brain. Although it is increasingly evident that the clocks in each of the neuronal clusters are regulated differently, how these clocks communicate with each other across the circadian neuronal network is less clear. Here, we review the latest evidence that describes the physical connectivity of the circadian neuronal network . Using small ventral lateral neurons as a starting point, we summarize how one clock may communicate with another, highlighting the signaling pathways that are both upstream and downstream of these clocks. We propose that additional efforts are required to understand how temporal information generated in each circadian neuron is integrated across a neuronal circuit to regulate rhythmic behavior.
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Franco, D. Lorena, Lia Frenkel, and M. Fernanda Ceriani. "The Underlying Genetics of Drosophila Circadian Behaviors." Physiology 33, no. 1 (January 1, 2018): 50–62. http://dx.doi.org/10.1152/physiol.00020.2017.
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Life is shaped by circadian clocks. This review focuses on how behavioral genetics in the fruit fly unveiled what is known today about circadian physiology. We will briefly summarize basic properties of the clock and focus on some clock-controlled behaviors to highlight how communication between central and peripheral oscillators defines their properties.
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Ben-Moshe, Zohar, Nicholas S. Foulkes, and Yoav Gothilf. "Functional Development of the Circadian Clock in the Zebrafish Pineal Gland." BioMed Research International 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/235781.
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The zebrafish constitutes a powerful model organism with unique advantages for investigating the vertebrate circadian timing system and its regulation by light. In particular, the remarkably early and rapid development of the zebrafish circadian system has facilitated exploring the factors that control the onset of circadian clock function during embryogenesis. Here, we review our understanding of the molecular basis underlying functional development of the central clock in the zebrafish pineal gland. Furthermore, we examine how the directly light-entrainable clocks in zebrafish cell lines have facilitated unravelling the general mechanisms underlying light-induced clock gene expression. Finally, we summarize how analysis of the light-induced transcriptome and miRNome of the zebrafish pineal gland has provided insight into the regulation of the circadian system by light, including the involvement of microRNAs in shaping the kinetics of light- and clock-regulated mRNA expression. The relative contributions of the pineal gland central clock and the distributed peripheral oscillators to the synchronization of circadian rhythms at the whole animal level are a crucial question that still remains to be elucidated in the zebrafish model.