A biochemical model of the circadian clock.
Explore the source record for details and available documents.
Adenosine Monophosphate↗
SEARCH · PubMed Health
Results for “Circadian clock”
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Genetic and physiological characteristics of a slow-growing circadian clock mutant of Neurospora crassa.
A circadian clock mutant of Neurospora crassa with a period length of about 25.8 hours (4 hr longer than wild type) has been isolated after mutagenesis of the band strain. This mutant, called frq-5, segregates as a single nuclear gene, maps near the centromere on linkage group III, and is unlinked to four previously described clock mutants clustered on linkage group VII R (Feldman and Hoyle 1973, 1976). frq-5 differs from the other clock mutants in at least two other respects: (1) it is recessive in heterokaryons, and (2) it grows at about 60% the rate of the parent band strain on both minimal and complete media. Double mutants between frq-5 and each of the other clock mutants show additivity of period length--two long period mutants produce a double mutant whose period length is longer than either of the two single mutants, while a long and a short period double mutant has an intermediate period length. Although slow growth and long periodicity of frq-5 have segregated together among more than 300 progeny, slow growth per se is not responsible for the long period, since all the double mutants have the slow growth characteristic of frq-5, but have period lengths both shorter and longer than wild type.
Circadian Rhythm↗
The circadian clock proteins PRR modulate root hair development via the RHD6/RSL module in Arabidopsis.
Root hairs, derived from trichoblasts, are critical for plant growth and environmental adaptation. Although environmental cues are known to influence root hair development, how endogenous timing systems such as the circadian clock integrate into the core transcriptional network governing root hair formation remains unclear. Here, we show that the circadian clock-associated protein PSEUDO-RESPONSE REGULATOR5 (PRR5) physically interacts with ROOT HAIR DEFECTIVE6 (RHD6) and RHD6 LIKE1 (RSL1), two basic helix-loop-helix transcription factors essential for root hair initiation. Genetic analyses suggest that PRR proteins contribute to root hair development under long-day conditions in Arabidopsis thaliana. Simultaneous disruption of PRR5, PRR7, and PRR9 results in defective root hairs, whereas PRR5 overexpression markedly increases root hair density and length. Transcriptomic and RT-qPCR analyses reveal that PRRs enhance the expression of RHD6, RSL1, and multiple downstream root hair-responsive genes, while modulating their temporal expression patterns. Furthermore, PRR5-mediated root hair promotion requires RHD6/RSL1, and PRR proteins enhance RHD6-dependent activation of the RSL4 promoter. PRRs also contribute to root hair development under phosphate-deficient and salt-stress conditions. Together, these findings establish a molecular framework in which PRR proteins regulate the RHD6/RSL network to coordinate root hair development and environmental responses.
Arabidopsis↗
Mapping the regulatory architecture of circadian clock adaptation: A genome-wide eQTL analysis in Drosophila melanogaster.
The circadian clock enables organisms to align internal daily rhythms with environmental cues, with major consequences for survival and fitness. Although the molecular framework of this system in Drosophila melanogaster is well characterized through transcription translation feedback loops involving ten core clock genes, the genetic basis of natural variation in their expression remains poorly understood. Here, we used natural expression variation to identify expression quantitative trait loci (eQTLs) through genome-wide association mapping. Using the Drosophila Genetic Reference Panel, we measured relative expression of all core clock genes at a single time point two hours after light onset. We identified 109 significant SNPs and 28 indels associated with expression variation across the clock network. Expression levels varied widely, with Pdp1ε showing the greatest variation (an 86-fold difference between extreme lines) and cyc the least (11.3-fold). Only three significant SNPs were located within clock genes themselves, all in Clk, whereas most associations represented trans-eQTLs in genes with diverse molecular functions. Candidate regulators included transcription factors such as Abd-B, tai, and E5; RNA binding proteins including Pum, Bru-3, and Mbl; and several long noncoding and antisense RNAs. Variants were also detected in gbb and the BMP pathway transcription factor Mad. Consistent with this, Mad knockdown reduced vri expression. Together, these results reveal a complex regulatory architecture underlying natural variation in circadian gene expression.
Journal Article↗
Circadian clock control of ribosome composition promotes rhythmic translation and termination fidelity.
Ribosome composition is dynamic, shifting with cell state and stress, but whether it varies with circadian time is unknown. Here, we uncover circadian clock-driven changes in ribosome composition in Neurospora crassa. Mass spectrometry of ribosomes across circadian time identified six ribosomal proteins and one associated factor under clock control. Rhythms in eL31 abundance were validated in purified ribosomes, and deletion of el31 disrupted translation rhythms in nearly half of rhythmically translated mRNAs. N. crassa eL31 promotes circadian control of translation termination and impacts elongation fidelity while maintaining Mg homeostasis, a key determinant of translational accuracy. These findings reveal that the circadian clock reprograms ribosome composition to orchestrate rhythmic translation and fidelity, temporally expanding the proteome beyond the static genome to align cellular function with time of day.
Neurospora crassa↗
The role of chloroplast-membrane-protein synthesis in the circadian clock. Purification and partial characterization of a polypeptide which is suggested to be involved in the clock.
A polypeptide (polypeptide P39), which is presumed to involved in the photosynthetic circadian rhythm in the green alga Acetabularia, was purified from the EDTA-insoluble chloroplast membrane fraction by means of preparative dodecylsulfate gel electrophoresis and then partially characterized. The purity of the isolated polypeptide P39 was confirmed by a further electrophoresis on an analytical dodecylsulfate gel and further elucidated by amino-terminal analysis which shows that glycine is the only amino-terminal amino acid of the purified polypeptide material. The molecular weight of the polypeptide P39 was found to be about 39,000 on analytical gel electrophoresis and the value was further supported by those obtained from amino acid composition and peptide mapping. The amino acid composition of polypeptide P39 showed that the proportion of intermediate amino acid groups is high while the proportion of hydrophilic amino acid groups is well balanced by that of hydrophobic amino acid groups, a property characteristic of membrane proteins.
Acetabularia↗
Mathematical modeling of dietary timing- and protein quality-responsive liver circadian clock and its function on ribosome biogenesis.
Independent of the suprachiasmatic nucleus, peripheral clocks can be strongly entrained by dietary signals. Although feeding time has been widely studied, the effects of food quality-particularly nutrient availability and stress-on peripheral circadian entrainment and metabolic regulation remain less understood. We developed a semimechanistic mathematical model of peripheral clock synchronization and clock-controlled ribosome biogenesis (RiBi) in response to feeding/fasting cycles and rhythms in dietary essential amino acid (EAA) availability. The model integrates EAA-sensitive signaling through mammalian target of rapamycin complex 1 (mTORC1) and the general control nonderepressible 2 (GCN2)-mediated integrated stress response (ISR), together with ribosomal protein expression as a metabolic endpoint. We used the model to examine circadian entrainment under nutrient stress, adaptation during transitions between feeding schedules with EAA insufficiency, and stress-related mechanisms that may restore circadian and metabolic function. Simulations showed that mTORC1 and GCN2-ISR signaling jointly regulate metabolic entrainability and stress adaptation and are required to maintain circadian synchronization and RiBi dynamics during nutrient stress. The model also predicted that differences in homeostatic adaptation can produce individualized recovery trajectories after transient dietary disruption. Finally, appropriate modulation of GCN2-ISR signaling mitigated disruption-associated RiBi hyperactivation by leveraging dietary EAA rhythms to restore clock function. These findings identify dietary EAA stress and its regulatory pathways as important determinants of peripheral circadian entrainment and metabolic adaptation, supporting the development of personalized nutrition-based strategies for circadian disruption-related chronic disease.NEW & NOTEWORTHY This study provides a mechanistic modeling framework linking dietary protein quality, EAA-sensitive mTORC1/GCN2-ISR signaling, peripheral circadian entrainment, and ribosome biogenesis, highlighting how nutrient stress may shape individualized circadian recovery and metabolic regulation.
Circadian Clocks↗
Complementation analysis of linked circadian clock mutants of Neurospora crassa.
A fourth mutant of Neurospora crassa, designated frq-4, has been isolated in which the period length of the circadian conidiation rhythm is shortened to 19. +/- 0.3 hours. This mutant is tightly linked to the three previously isolated frq mutants, and all four map to the right arm of linkage group VII about 10 map units from the centromere. Complementation tests suggest, but do not prove, that all four mutations are allelic, since each of the four mutants is co-dominant with the frq+ allel--i.e., heterokaryons have period lengths intermediate between the mutant and wild-type--and since heterokaryons between pairs of mutants also have period lengths intermediate between those of the two mutants.
Alleles↗
Temperature sensitive events between photoreceptor and circadian clock?
The phase shifting action of low temperature pulses of 6 degrees C and 2 h duration administered to the various phases of the Drosophila pseudoobscura circadian rhythm and the action of light pulses given 30 min after the beginning of these low temperature pulses have been investigated. The phase response curve obtained from experiments with light pulses during low temperature cannot be explained on the basis of a straightforward and sequential phase shifting of the oscillation by the various transitions in the pulses. The response curve, after the slight phase shifting action of the temperature pulses is corrected for, resembles the standard phase response curve4 for light pulses (at 20 degrees C) in its wave form but not in its time course. Our curve is shifted in time in a manner that indicates that the light pulses accompanying the low temperature pulses arrived at phase points 1.5 h later than the actual phases at which they were given. We attribute this delay to a slowing down of the information that is apparently transmitted by a process that is temperature dependent.
Animals↗
11β-HSD2 buffers fetal glucocorticoid exposure inducing Per1 expression under maternal stress.
Glucocorticoids (GCs) have been proposed as maternal-fetal communication signals. However, fetal circadian rhythms are initially shielded from maternal entrainment, in addition to delayed circadian clock emergence due to CLOCK suppression. Premature CLOCK/BMAL1 activation disrupts Hes7-driven somite-like structure in gastruloids. Given the genomic proximity of Per1 to Hes7 and their transcriptional ripple effect, the physiological significance of delayed cell-autonomous circadian clock development and the temporal program of maternal-fetal communication during the developmental process has remained unclear. Here, based on a marked decline in Hsd11b2, encoding a GC-inactivating 11β-HSD2 enzyme, during organogenesis, we performed split-litter embryo-transfer experiments in which Hsd11b2 knockout (KO) and wild-type embryos shared the same maternal environment. Amniotic fluid GCs remained low and arrhythmic under basal conditions. In contrast, maternal stress caused a pronounced GC surge and Per1 induction in KO, suggesting that 11β-HSD2 buffers acute maternal GC surges. Despite the genomic proximity of Per1 to Hes7 and their transcriptional ripple effect, stress-associated and pharmacological GC exposure recapitulated no overt segmentation defects in vivo. Embryonic stem cell-derived gastruloid assays confirmed that neither GC exposure nor Per1 induction arrested Hes7 oscillations, whereas premature CLOCK/BMAL1 activation impaired these processes even in Hes7 KO gastruloid with ectopic rescue, suggesting that interference with the segmentation clock is mediated by premature CLOCK/BMAL1 activation, not by GC-induced Per1 expression. These findings clearly show that maternal GC signals are selectively buffered during early development. In addition, suppression of CLOCK/BMAL1 activity preserves segmentation clock function, indicating delayed circadian clock emergence is actively regulated during embryogenesis.
11β-HSD2↗
Gene editing of clock components in Solanum lycopersicum: Effects on gene expression, development, and productivity.
The circadian clock plays a crucial role in regulating key biological processes, including growth and development. While studies in the model plant Arabidopsis thaliana have significantly advanced our understanding of circadian function, recent research has also focused on crop species for improved yield and quality. In this study, we examined the rhythmic behavior and regulatory function of circadian clock components in tomato (Solanum lycopersicum). Time course analyses of gene expression over the circadian cycle revealed robust rhythmic oscillations in tomato leaves under free-running conditions. Comparative analyses showed similar peak phases for several clock genes in Arabidopsis and tomato, suggesting functional conservation. Rhythms in tomato fruits, however, showed reduced amplitude, slight phase changes, or arrhythmia, indicating organ-specific circadian variations. By using CRISPR-Cas9 gene editing strategies (clockcrispr), we also showed that proper clock gene expression is essential for setting the phase in tomato plants. Leaf movement analyses also showed a phase change in the clockcrispr lines, correlating with shorter or longer periods. The clockcrispr lines also displayed distinct growth and developmental phenotypes that differ from those reported in the Arabidopsis clock mutant counterparts. Our transcriptomic analyses identified species-specific regulation of key target genes. The results offer mechanistic insights into the conserved and divergent molecular pathways governing circadian phenotypic variations between Arabidopsis and tomato plants.
Solanum lycopersicum↗
Circadian- and light-regulated oscillatory expression of CSA in rice leaves is required for pollen fertility.
The oscillatory expression of CSA in rice leaves is regulated by the circadian clock and red/far-red light signals, mediated through DOF5 and PIL11, and is required for normal pollen fertility. Photoperiod-sensitive male-sterile lines represent a pivotal innovation in the development of hybrid rice. However, the underlying mechanisms governing photoperiod-sensitive male reproductive development remain poorly understood. Our previous studies demonstrated that the carbon starved anther (csa) mutant exhibits male sterility under short-day (SD) conditions but partial fertility under long-day (LD) conditions. In this study, we report that CSA expression follows an oscillatory rhythm in rice leaves under both SD and LD conditions, a pattern regulated by both circadian clock and light signals. Tissue-specific RNA interference knockdown of CSA in leaves was associated with reduced pollen viability, suggesting that CSA expression in leaves contributes to normal male fertility. Promoter truncation assay results indicate that distinct regions of the CSA promoter contribute differentially to the regulation of CSA expression in leaves versus anthers, and that both the CSA expression level in anthers and the rhythmic expression pattern of CSA in leaves are associated with the restoration of male fertility. Using dual-luciferase, yeast one-hybrid, and electrophoretic mobility shift assays, we identified two proteins, PIL11 and DOF5, which directly bind to specific motifs (an E-box and T/AAAAG motif) within the CSA promoter truncation, thereby regulating its transcription. These findings elucidate novel mechanisms linking light sensing to the expression of circadian-controlled genes, thus connecting photoperiod with male reproductive development in rice.
Oryza↗
Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.
Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms.
Tumor Microenvironment↗
40S Ribosomal protein S6 kinase integrates daylength perception and growth regulation in Arabidopsis thaliana.
Plant growth occurs via the interconnection of cell growth and proliferation in each organ following specific developmental and environmental cues. Therefore, different photoperiods result in distinct growth patterns due to the integration of light and circadian perception with specific Carbon (C) partitioning strategies. In addition, the TARGET OF RAPAMYCIN (TOR) kinase pathway is an ancestral signaling pathway that integrates nutrient information with translational control and growth regulation. Recent findings in Arabidopsis (Arabidopsis thaliana) have shown a mutual connection between the TOR pathway and the circadian clock. However, the mechanistical network underlying this interaction is mostly unknown. Here, we show that the conserved TOR target, the 40S ribosomal protein S6 kinase (S6K) is under circadian and photoperiod regulation both at the transcriptional and post-translational level. Total S6K (S6K1 and S6K2) and TOR-dependent phosphorylated-S6K protein levels were higher during the light period and decreased at dusk especially under short day conditions. Using chemical and genetic approaches, we found that the diel pattern of S6K accumulation results from 26S proteasome-dependent degradation and is altered in mutants lacking the circadian F-box protein ZEITLUPE (ZTL), further strengthening our hypothesis that S6K could incorporate metabolic signals via TOR, which are also under circadian regulation. Moreover, under short days when C/energy levels are limiting, changes in S6K1 protein levels affected starch, sucrose and glucose accumulation and consequently impacted root and rosette growth responses. In summary, we propose that S6K1 constitutes a missing molecular link where day-length perception, nutrient availability and TOR pathway activity converge to coordinate growth responses with environmental conditions.
Arabidopsis↗
Developmental roles of LSD1/KDM1A-like (LDL) proteins in plants.
LYSINE-SPECIFIC DEMETHYLASE 1-like (LDL) proteins are conserved FAD-dependent amine oxidases that serve as pivotal regulators in plants. While animal systems typically rely on a single LSD1/KDM1A enzyme, the Arabidopsis thaliana genome encodes an expanded family of LDL homologues (FLD, LDL1, LDL2, and LDL3), resulting in substantial subfunctionalization and specialized recruitment mechanisms. This review explores the diverse developmental roles of plant LDLs, ranging from flowering time and circadian clock regulation to heterochromatin maintenance and epigenetic regulation. We discuss the redundant roles of FLD, LDL1, and LDL2 in repressing the floral repressor FLC and their nonredundant specialized function within the CCA1/LHY-TOC1 circadian feedback loop. A central focus of our review is the emerging mechanism of transcription-coupled demethylation, in which LDLs associate with the phosphorylated C-terminal domain of RNA polymerase II to modify chromatin cotranscriptionally within gene bodies. By integrating findings from Arabidopsis thaliana and crops such as tomato and soybean, we illustrate how the diversified LDL-mediated regulatory toolkit facilitates precise, gene-specific regulation. Ultimately, the LDL family represents a cornerstone of the sophisticated epigenetic strategies that regulate plant phenotypic plasticity in response to developmental and environmental cues.
Circadian clock↗
GIRK Channels Regulate Circadian Rhythms of Excitability in Prokineticin 2 Neurons of the Suprachiasmatic Nucleus and Modulate Behavioral Circadian Rhythms.
The suprachiasmatic nucleus (SCN), the central circadian clock in mammals, generates robust yet adaptable circadian rhythms through electrically mediated coordination among heterogeneous peptidergic neuronal populations with presumed cell type-specific roles. Previous studies have proposed that circadian changes in membrane excitability of individual SCN neurons arise from time-of-day-dependent shifts in the relative balance of subthreshold Na+ and K+ conductances. Although multiple channels have been implicated in these processes, how nocturnally dominant K+ conductances are implemented in a cell type-specific manner remains poorly understood. Prokineticin 2 (Prok2) has been identified as a SCN signaling peptide essential for behavioral circadian regulation; however, the electrophysiological properties of Prok2-expressing neurons and the mechanisms underlying their diurnal rhythmicity remain largely unexplored. Here, using electrophysiological approaches in mice of either sex, we show that Prok2 neurons exhibit diurnal variations in electrical properties, with higher excitability during the day and reduced excitability at night, and that G-protein-coupled inwardly rectifying potassium (GIRK) channel-mediated basal current contributes to nighttime hyperpolarization. Immunofluorescence and single-cell RT-PCR analyses revealed that GIRK1 and GIRK3 are the predominant GIRK subunits expressed in Prok2 neurons. Moreover, Prok2 neuron-specific deletion of GIRK3 using in vivo genome editing resulted in significant nocturnal depolarization and induced abnormalities in behavioral rhythms, including delayed activity onset and circadian period lengthening, with altered SCN network activity. Together, these findings suggest that tonic, G-protein-dependent regulation of GIRK channels provides a night-specific inhibitory mechanism that contributes to intrinsic diurnal neuronal excitability in Prok2 neurons and supports the regulation of behavioral circadian rhythms.
Animals↗
O-GlcNAcylation of nuclear proteins in the mouse liver exhibit daily oscillations that are influenced by meal timing.
The liver circadian clock and hepatic transcriptome are highly responsive to metabolic signals generated from feeding-fasting rhythm. Previous studies have identified a number of nutrient-sensitive signaling pathways that could interpret metabolic input to regulate rhythmic hepatic biology. Here, we investigated the role of O-GlcNAcylation, a nutrient-sensitive post-translational modification (PTM) in mediating metabolic regulation of rhythmic biology in the liver. We observe daily oscillation of global nuclear protein O-GlcNAcylation in the liver of mice subjected to night-restricted feeding (NRF) using label-free global O-GlcNAc proteomics. Additional site-specific O-GlcNAc analysis by tandem mass tag mass spectrometry further supports temporal differences in O-GlcNAcylation by revealing day-night differences. Proteins involved in gene expression are enriched among rhythmically O-GlcNAcylated proteins, suggesting rhythmic O-GlcNAcylation may directly regulate the hepatic transcriptome. We show that rhythmic O-GlcNAcylation can also indirectly modulate nuclear proteins by interacting with phosphorylation. Several proteins harboring O-GlcNAcylation-phosphorylation interplay motif exhibit rhythmic O-GlcNAcylation and phosphorylation. Specifically, we show that O-GlcNAcylation occurs at a phospho-degron of a key circadian transcriptional activator, circadian locomotor output cycles kaput (CLOCK), thus regulating its stability and transcriptional output. Finally, we report that day-restricted feeding (DRF) in the nocturnal mouse significantly alters O-GlcNAcylation pattern. Whereas global O-GlcNAcylation analysis indicates dampening of global O-GlcNAcylation rhythm in mice fed under DRF, site-specific analysis reveals differential responses of O-GlcNAc sites when timing of food intake is altered. Notably, a substantial number of O-GlcNAcylation sites exhibit inverted day-night profiles when mice are subjected to DRF. This suggests the dysregulation of daily nuclear protein O-GlcNAcylation rhythm may contribute to the disruption in liver transcriptome previously observed in DRF condition. In summary, our results provide new mechanistic insights into metabolic regulation of hepatic transcriptional regulators via interplay between O-GlcNAcylation and phosphorylation and shed light on the deleterious effects of improper mealtimes.
Animals↗
Rhythm profiling using COFE reveals multi-omic circadian rhythms in human cancers in vivo.
The study of ubiquitous circadian rhythms in human physiology requires regular measurements across time. Repeated sampling of the different internal tissues that house circadian clocks is both practically and ethically infeasible. Here, we present a novel unsupervised machine learning approach (COFE) that can use single high-throughput omics samples (without time labels) from individuals to reconstruct circadian rhythms across cohorts. COFE can simultaneously assign time labels to samples and identify rhythmic data features used for temporal reconstruction, while also detecting invalid orderings. With COFE, we discovered widespread de novo circadian gene expression rhythms in 11 different human adenocarcinomas using data from The Cancer Genome Atlas (TCGA) database. The arrangement of peak times of core clock gene expression was conserved across cancers and resembled a healthy functional clock except for the mistiming of a few key genes. Moreover, rhythms in the transcriptome were strongly associated with the cancer-relevant proteome. The rhythmic genes and proteins common to all cancers were involved in metabolism and the cell cycle. Although these rhythms were synchronized with the cell cycle in many cancers, they were uncoupled with clocks in healthy matched tissue. The targets of most of FDA-approved and potential anti-cancer drugs were rhythmic in tumor tissue with different amplitudes and peak times. These findings emphasize the utility of considering "time" in cancer therapy, and suggest a focus on clocks in healthy tissue rather than free-running clocks in cancer tissue. Our approach thus creates new opportunities to repurpose data without time labels to study circadian rhythms.
Humans↗