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At least 451 records · Page 25Linked to original sources
PubMed2004

Circadian clocks and natural antisense RNA.

Eukaryotes regulate gene expression in a number of different ways. On a daily and seasonal timescale, the orchestration of gene expression is to a large extent governed by circadian clocks. These endogenous timekeepers enable organisms to prepare for predictable environmental conditions from one day to the next and thus allow adaptation to a given temporal niche. In general, circadian clocks have been shown to employ the classical transcriptional and posttranscriptional control mechanisms to generate rhythmicity. However, the discovery of antisense clock gene transcripts suggests that mechanisms of gene regulation operating through antisense RNA may also be integral to the circadian clockwork. Following a brief history of the impact of genetic and molecular techniques in aiding our understanding of circadian clocks, this review concentrates on the few examples of antisense clock gene transcripts so far investigated and their effect on circadian timing.

Animals↗
PubMed2005

A functional subdivision of the circadian clock is revealed by differential effects of melatonin administration.

The biological clock of the suprachiasmatic nuclei drives numerous physiological and behavioural circadian rhythms. In this study, we addressed the question as to whether different components of the clock may control separately various circadian functions. Using the rat transpineal microdialysis tool, we analysed the effect of clock perturbation by exogenous melatonin injection on two hormonal clock outputs: pineal melatonin and adrenal corticosterone secretions. As already reported, a single melatonin injection at the light/dark transition induces a marked increase in the endogenous pineal melatonin peak for the two following days. In the same animals, by contrast, the amplitude of the corticosterone rhythm was not altered following melatonin injection. These data show that the melatonin injection does not display an overall effect on the circadian clock, but rather influences a subpopulation of melatonin-sensitive neurons involved, among other functions, in the circadian control of the pineal pathway.

Adrenal Cortex↗
PubMed2001

Posttranslational mechanisms regulate the mammalian circadian clock.

We have examined posttranslational regulation of clock proteins in mouse liver in vivo. The mouse PERIOD proteins (mPER1 and mPER2), CLOCK, and BMAL1 undergo robust circadian changes in phosphorylation. These proteins, the cryptochromes (mCRY1 and mCRY2), and casein kinase I epsilon (CKIepsilon) form multimeric complexes that are bound to DNA during negative transcriptional feedback. CLOCK:BMAL1 heterodimers remain bound to DNA over the circadian cycle. The temporal increase in mPER abundance controls the negative feedback interactions. Analysis of clock proteins in mCRY-deficient mice shows that the mCRYs are necessary for stabilizing phosphorylated mPER2 and for the nuclear accumulation of mPER1, mPER2, and CKIepsilon. We also provide in vivo evidence that casein kinase I delta is a second clock relevant kinase.

Animals↗
PubMed1995

Light-induced resetting of a circadian clock is mediated by a rapid increase in frequency transcript.

To understand how light entrains circadian clocks, we examined the effects of light on a gene known to encode a state variable of a circadian oscillator, the frequency (frq) gene. frq is rapidly induced by short pulses of visible light; clock resetting is correlated with frq induction and is blocked by drugs that block the synthesis of protein or translatable RNA. The speed and magnitude of frq induction suggest that this may be the initial clock-specific event in light resetting. Light induction overcomes frq negative autoregulation so that frq expression can remain high in constant light. These data explain how a simple unidirectional signal (light and the induction of frq) may be turned into a bidirectional clock response (time of day-specific advances and delays). This light entrainment model is easily generalized and may be the common mechanism by which the intracellular feedback cycles that comprise circadian clocks are brought into synchrony with external cycles in the real world.

Analysis of Variance↗
PubMed1997

The utility of the ten-point clock test as a screen for cognitive impairment in general hospital patients.

The object of this work was to illustrate the utility of the ten-point clock test as a screen for cognitive impairment in the general hospital by examining a range of diagnoses and estimating sensitivity for each. A total of 195 consecutive medical and surgical inpatients were examined who were referred for psychiatric consultation and histories from patient, family, nurses, physicians, and hospital records were obtained. Seventy-six percent of these patients were administered the ten-point clock test at the initial evaluation. The percentages of patients scoring less than 8 points on the ten-point clock test for the following primary diagnoses were delirium (92%), dementia (90%), and adjustment disorder (5%). Thirty-nine to seventy percent of patients with a delirium, dementia, opioid intoxication, or a cognitive disorder n. o. s. scored lower than 5 points but none of the patients with a major depressive disorder, alcohol dependence, or adjustment disorder did so. The sensitivities of the ten-point clock test and minimental state examinations appeared similar in a subset of patients. The ten-point clock test is a useful screen for cognitive impairment in general hospital patients.

Adult↗
PubMed2000

Circadian rhythms: new functions for old clock genes.

The mechanisms of circadian clocks, which time daily events, are being investigated by characterizing 'clock genes' that affect daily rhythms. The core of the clock mechanism in Drosophila, Neurospora, mammals and cyanobacteria is described by a transcription-translation feedback-loop model. However, problems with this model could indicate that it is time to look at the functions of these genes in a different light. Our a priori assumptions about the nature of circadian clocks might have restricted our search for new mutants in ways that prevent us from finding important clock genes.

Acetabularia↗
PubMed2003

Expression of the transcriptional coactivators CBP and p300 in the hamster suprachiasmatic nucleus: possible molecular components of the mammalian circadian clock.

Immediate early genes are expressed in the mammalian suprachiasmatic nucleus in response to photic information arriving from the retina at restricted times of the day, therefore their expression is regulated by the circadian biological clock. These light-induced genes are also activated by the phosphorylated form of CREB (pCREB) that binds to a cAMP response element upstream of the genes. The nuclear proteins CBP and p300 are known to be coactivators with pCREB in certain cell types, but their identification within the rodent SCN has not been reported. Therefore, in this study we examined the distribution of both CBP and p300 in the hamster suprachiasmatic nucleus. CBP and p300 immunoreactivity is detected in cells throughout the suprachiasmatic nucleus, and the pattern of staining within cells is indicative of a nuclear location for these proteins. The number of cells immunoreactive for both CBP and p300 significantly decreases at mid-night circadian times with respect to mid-day circadian times, although the reduction is less than 20%. Neither CBP nor p300 expression is affected by a circadian phase-resetting light pulse given late in the night. The ability of CBP and p300 to interact with pCREB as well as with the clock gene BMAL1 is discussed, and we propose that CBP and p300 may interact with, and link, both clock genes and clock-controlled genes in the generation of circadian rhythms in mammals. We further suggest that there will be a general importance for the role of transcriptional coactivators such as CBP and p300 in many of the molecular pathways related to the mammalian circadian clock.

ARNTL Transcription Factors↗
PubMed2003

Contrary to other non-photic cues, acute melatonin injection does not induce immediate changes of clock gene mRNA expression in the rat suprachiasmatic nuclei.

The suprachiasmatic nuclei (SCN) contain the main clock of the mammalian circadian system. The endogenous oscillation machinery involves interactive positive and negative transcriptional and posttranslational feedback loops involving the clock genes Per1, Per2, Per3, Clock, Bmal1, Cry1 and Cry2. The SCN endogenous oscillation is entrained to 24 h by the light/dark cycle. Light induced regulation of Per1 and Per2 mRNA expression have been suggested to take part in the clock resetting. However, other factors have chronobiotic and synchronizing effects on SCN activity. Especially, the nocturnal pineal gland hormone, melatonin, which is involved in the regulation of both circadian and seasonal rhythms, is known to feedback on the SCN. Melatonin applied on SCN slices immediately phase-shifts their neuronal electrical activity, while daily injections of melatonin to free running rodents resynchronize their locomotor activity to 24 h. To determine whether melatonin feedback control on SCN activity implicates transcriptional regulation of the clock genes, we monitored the expression pattern of Per 1, 2, 3, Bmal1, Cry1 and AVP mRNAs after a single melatonin injection at the end of the subjective day. Results showed that melatonin injection affected none of the mRNA expression pattern during the first circadian night. Per1, Per3, Bmal1 and AVP expression patterns were, however, significantly but differentially affected, during the second subjective night after the melatonin injection. The present results strongly suggest that the immediate phase shifting effect of melatonin on the SCN molecular loop implicates rather post-translational than transcriptional mechanisms.

ARNTL Transcription Factors↗
PubMed1998

Conditioned fear suppresses light-induced resetting of the circadian clock.

The possibility that circadian rhythms can be modulated by emotional state is suggested by clinical evidence of altered physiological and endocrine rhythms in primary depression and related affective disorders and is supported by experiments in humans and laboratory animals showing that stress disrupts circadian rhythmicity. How emotional state might modulate circadian rhythms is not known. Here we report that induction of the emotional state of fear disrupts a process essential for stable entrainment of circadian rhythms, the resetting of the circadian clock by environmental light. A cellular correlate of light-induced clock resetting, expression of the transcription factor Fos in the suprachiasmatic nucleus of the hypothalamus (the circadian clock), and a behavioral measure of clock resetting, phase shifts in free-running activity rhythms, were found to be suppressed in rats exposed to light in a context made to induce fear by previous pairings with intermittent footshock. These findings show that fear disrupts a physiological process mediating light-induced clock resetting and suggest a mechanism through which emotional state could modulate circadian rhythms.

Animals↗
PubMed2002

Environmental stimulus perception and control of circadian clocks.

Circadian rhythms are regulated by clocks located in specific structures of the central nervous system, such as the suprachiasmatic nucleus (SCN) in mammals, and by peripheral oscillators present in various other tissues. Recent discoveries have elucidated the control of central and peripheral clocks by environmental signals. The major synchroniser in animals is light. In mammals, a subset of retinal ganglion cells receive light signals that are transmitted to the SCN via the retinohypothalamic tract. Photoreception is probably elicited by a novel opsin, melanopsin, although cryptochromes may also play a role. These signals feed directly to the SCN master clock, which then provides timing cues to peripheral clocks. In contrast to mammals, peripheral tissues in the fly and in the fish are directly photoreceptive. However, alternative routes exist. Some peripheral clocks in mammals can be specifically entrained in an SCN-independent manner by restricting food during the light period.

Animals↗
PubMed1999

The circadian clocks of plants and cyanobacteria.

Classical research on the circadian rhythms of plants helped to demonstrate that all living organisms utilize circadian clocks to adapt their day-night cycles and that the clock is the basis for photoperiodic time measurements. Molecular models for the circadian oscillator have now been elucidated in Drosophila, Neurospora, mice and cyanobacteria. All share a similar feedback structure, but key proteins in each of the oscillators are different. A plant clock model has yet to be proposed, but clock mutants of Arabidopsis are expected to reveal key proteins in the mechanism. Here we discuss how a self-sustained oscillation is established in eukaryotic and prokaryotic models, and the polyphyletic evolution of these clock systems.

Journal Article↗
PubMed2002

Assessing the relative importance of light and the circadian clock in controlling chloroplast translation in Chlamydomonas reinhardtii.

Previous work has shown that transcription of a number of chloroplast-encoded genes, including those for photosynthesis, are under circadian clock control in Chlamydomonas reinhardtii. However, some of these genes encode long-lived mRNAs that are also subject to translational control. Rates of synthesis of the major chloroplast translation products vary dramatically (10-20-fold) during light-dark (LD) cycles, peaking in the light period. To determine whether this pattern reflects circadian clock control, LD-grown cells were shifted to continuous light (LL) and chloroplast protein synthesis monitored by periodic pulse-labeling in the presence of cycloheximide; chloroplast protein synthesis in LD was also examined for comparison. The LD patterns of synthesis of the major polypeptides (including D1, D2, and the large subunit of ribulose-1,5-bisphosphate carboxylase (LS)) were similar to those obtained previously in the absence of cycloheximide. In the LL condition, rates of synthesis of the major chloroplast translation products were high throughout the period examined ( approximately 36 h), fluctuating > 3-fold, although they were generally higher in the subjective light period. LD-grown cells were also shifted to continuous dark (DD) and chloroplast protein synthesis analyzed for approximately 24 h starting from the mid-dark period. There was a gradual decline in synthesis of the major proteins during the first subjective light period, which was followed by a very small peak in synthesis around the second subjective dark --> light transition. RNA blot analysis showed that the mRNAs for D1, D2 and LS were present at high levels during the period of declining translation. These results indicate that with photoautotrophic growth in LD cycles, the illumination conditions per se are more important than the clock in determining chloroplast translation, but the clock may contribute to this regulation. The advantages of controlling translation by a direct light response and transcription primarily by the circadian clock are discussed. Finally, evidence of translational control of elongation factor Tu synthesis was obtained.

Journal Article↗
PubMed1980

Processing of visually presented clock times.

The encoding and representation of visually presented clock times was investigated in three experiments utilizing a comparative judgment task. Experiment 1 explored the effects of comparing times presented in different formats (clock face, digit, or word), and Experiment 2 examined angular distance effects created by varying positions of the hands on clock faces. In Experiment 3, encoding and processing differences between clock faces and digitally presented times were directly measured. Same/different reactions to digitally presented times were faster than to times presented on a clock face, and this format effect was found to be a result of differences in processing that occurred after encoding. Angular separation also had a limited effect on processing. The findings are interpreted within the framework of theories that refer to the importance of representational codes. The applicability to the data of Bank's semantic-coding theory, Paivio's dual-coding theory, and the levels-of-processing view of memory are discussed.

Discrimination Learning↗
PubMed2005

System-level identification of transcriptional circuits underlying mammalian circadian clocks.

Mammalian circadian clocks consist of complexly integrated regulatory loops, making it difficult to elucidate them without both the accurate measurement of system dynamics and the comprehensive identification of network circuits. Toward a system-level understanding of this transcriptional circuitry, we identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of their transcriptional dynamics. Here we report the roles of E/E' boxes, DBP/E4BP4 binding elements and RevErbA/ROR binding elements in nine, seven and six genes, respectively. Our results indicate that circadian transcriptional circuits are governed by two design principles: regulation of E/E' boxes and RevErbA/ROR binding elements follows a repressor-precedes-activator pattern, resulting in delayed transcriptional activity, whereas regulation of DBP/E4BP4 binding elements follows a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Our analysis further suggests that regulation of E/E' boxes is a topological vulnerability in mammalian circadian clocks, a concept that has been functionally verified using in vitro phenotype assay systems.

Animals↗
PubMed2026

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↗
PubMed2003

ATP-induced hexameric ring structure of the cyanobacterial circadian clock protein KaiC.

BACKGROUND: KaiA, KaiB and KaiC are cyanobacterial circadian clock proteins. KaiC contains two ATP/GTP-binding Walker's motif As, and mutations in these regions affect the clock oscillations. RESULTS: ATP induced the hexamerization of KaiC. The Km value for the ATP for the hexamerization was 1.9 micro m. Triphosphate nucleotides bound to the two Walker's motif As, and their binding functioned cooperatively for the hexamerization. An unhydrolysable substrate, 5'-adenylylimidodiphosphate (AMPPNP), also induced the hexamerization, indicating that nucleotide binding, but not its hydrolysis, is essential for the hexamerization. Mutations in each of the two Walker's motif As that affect the clock phenotype increased the Km value for ATP and inhibited the hexamerization. Thus, the KaiC hexamerization seems to be necessary for its clock function. The KaiC hexamer has the shape of a hexagonal pot with a diameter and height of approximately 100 A and with a relatively large cavity (73 A deep and 18-34 A wide) inside. This pot-shaped structure suggests that KaiC functions in a similar manner to F1-ATPase, helicase or ATP-dependent protease/chaperon, all of which have dynamic activities inside the central cavity of their hexameric rings. CONCLUSION: ATP-induced KaiC hexamerization is necessary for the clock function of KaiC.

Adenosine Triphosphate↗
PubMedDate not supplied

The vertebrate segmentation clock.

Vertebrate somitogenesis has been shown to be associated with a molecular oscillator, the segmentation clock, whose periodicity matches that of the process of somitogenesis. The existence of such a clock in presomitic mesoderm (PSM) cells was originally proposed in theoretical models such as the 'clock and wavefront'. Molecular evidence for the existence of this clock in vertebrates has been obtained on the basis of the periodic expression of several genes, most of which are related to the Notch signalling pathway. These genes are expressed in a dynamic sequence which appears as a wave sweeping caudo-rostrally along the whole PSM once during each somite formation. Notch-pathway mouse and fish mutants lose the dynamic expression of the cycling genes, indicating that Notch signalling is required for their periodic expression, or is required to coordinate the oscillations between PSM cells. Therefore Notch signalling is either part of the mechanism of the oscillator itself or acts as a cofactor required for cycling gene expression. A further potentially important role for the segmentation clock is to periodically activate Notch signalling in the rostral presomitic mesoderm, thereby generating the periodic formation of somite boundaries.

Animals↗
PubMed1994

Tryptophan hydroxylase expression is regulated by a circadian clock in Xenopus laevis retina.

A circadian clock has been localized to the photoreceptor layer in the Xenopus laevis retina. This clock controls the rhythmic synthesis of melatonin, which results in elevated levels during the night and low levels during the day. The rate-limiting enzyme in melatonin synthesis in Xenopus laevis retina is tryptophan hydroxylase. A cDNA clone coding for Xenopus tryptophan hydroxylase was isolated, characterized, and used as a probe for analysis of tryptophan hydroxylase mRNA expression. Northern blot analyses of total retinal RNA show that the tryptophan hydroxylase message levels are low in the day and higher at night. The expression of tryptophan hydroxylase mRNA is under circadian control because rhythmic changes are also seen in constant darkness, with elevated levels during the subjective night. Nuclear run-on analysis during the first subjective day in constant darkness revealed that transcription initiation is low early in the day and increases throughout the day. Our observations suggest that the circadian clock modulates tryptophan hydroxylase gene expression. An understanding of how the circadian clock controls tryptophan hydroxylase expression may lead to a clearer understanding of the melatonin biosynthetic pathway, and possibly the clock itself.

Amino Acid Sequence↗