• Animal cells and systems
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• v.16 no.1
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• pp.1-10
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• 2012

Most living organisms synchronize their physiological and behavioral activities with the daily changes in the environment using intrinsic time-keeping systems called circadian clocks. In mammals, the key molecular features of the internal clock are transcription- and translational-based negative feedback loops, in which clock-specific transcription factors activate the periodic expression of their own repressors, thereby generating the circadian rhythms. CLOCK and BMAL1, the basic helix-loop-helix (bHLH)/PAS transcription factors, constitute the positive limb of the molecular clock oscillator. Recent investigations have shown that various levels of posttranslational regulation work in concert with CLOCK/BMAL1 in mediating circadian and cellular stimuli to control and reset the circadian rhythmicity. Here we review how the CLOCK and BMAL1 activities are regulated by intracellular distribution, posttranslational modification, and the recruitment of various epigenetic regulators in response to circadian and cellular signaling pathways.

• Animal cells and systems
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• v.13 no.2
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• pp.119-125
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• 2009

Mammalian hibernation is a type of natural adaptation that allows organisms to avoid harsh environment and to increase the possibility of survival. To investigate the molecular link between circadian and hibernating rhythms in the greater tube-nosed bats, Murina leucogaster, we set out to identify circadian genes that are expressed in bats, with specific focus on the PAS domain by using PCR-based screens. We could isolate a eDNA clone, designated as LPAS1, that encodes a protein of 521 amino acid residues. LPAS1 is closely related with CLOCK family with the highest homology to human CLOCK. Based on RT-PCR analyses, LPAS1 transcripts are ubiquitously present in tissues from both summer active and winter dormant periods. Given that LPAS1 is a member of the bHLH-PAS protein superfamily but lacks polyglutamine transactivation domains, it is likely to function as a repressor for endogenous CLOCK to hinder its roles in promoting transcription. Our result will open a new avenue to further examine the functional interconnection between the circadian clock and the circannual clock such as mammalian hibernation.

• Molecules and Cells
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• v.39 no.1
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• pp.6-19
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• 2016

Redox signalling comprises the biology of molecular signal transduction mediated by reactive oxygen (or nitrogen) species. By specific and reversible oxidation of redoxsensitive cysteines, many biological processes sense and respond to signals from the intracellular redox environment. Redox signals are therefore important regulators of cellular homeostasis. Recently, it has become apparent that the cellular redox state oscillates in vivo and in vitro, with a period of about one day (circadian). Circadian timekeeping allows cells and organisms to adapt their biology to resonate with the 24-hour cycle of day/night. The importance of this innate biological timekeeping is illustrated by the association of clock disruption with the early onset of several diseases (e.g. type II diabetes, stroke and several forms of cancer). Circadian regulation of cellular redox balance suggests potentially two distinct roles for redox signalling in relation to the cellular clock: one where it is regulated by the clock, and one where it regulates the clock. Here, we introduce the concepts of redox signalling and cellular timekeeping, and then critically appraise the evidence for the reciprocal regulation between cellular redox state and the circadian clock. We conclude there is a substantial body of evidence supporting circadian regulation of cellular redox state, but that it would be premature to conclude that the converse is also true. We therefore propose some approaches that might yield more insight into redox control of cellular timekeeping.

• Journal of Life Science
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• v.33 no.9
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• pp.730-735
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• 2023

In the past decade, numerous studies have been carried out to quantify aging with the help of artificial intelligence. Using DNA methylation data, various models have been developed; these are commonly called epigenetic clocks. Epigenetic age acceleration is usually associated with disease conditions. Schizophrenia is a mental illness associated with severe mental and physical stress. This disease leads to high mortality and morbidity rates in young people compared with other psychological disorders. In the past, the research community considered this disease to be related to the accelerated aging hypothesis. In the current study, we wanted to investigate the epigenetic age acceleration changes in schizophrenia patients to obtain epigenetic insights into the disease. To measure the epigenetic age acceleration, we used two different DNA methylation clock models, namely, Horvath clock and Epi clock, as these are pan-tissue models. We utilized 450k array data compatible with both clocks. We found a slower epigenetic acceleration in the patients' samples when we used the Epi clock. We further analyzed the differentially methylated CpG sites between the control and cases and performed pathway enrichment analysis. We found that most of the CpGs are involved in neuronal processes.

• Journal of Life Science
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• v.27 no.10
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• pp.1225-1231
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• 2017

Disruptive expression patterns of the circadian clock genes are highly associated with many human diseases, including cancer. Cell cycle and proliferation is linked to a circadian rhythm; therefore, abnormal clock gene expression could result in tumorigenesis and malignant development. The molecular network of the circadian clock is based on transcriptional and translational feedback loops orchestrated by a variety of clock activators and clock repressors. The expression of 10~15% of the genome is controlled by the overall balance of circadian oscillation. Among the many clock genes, Period 1 (Per1) and Period 2 (Per2) are clock repressor genes that play an important role in the regulation of normal physiological rhythms. It has been reported that PER1 and PER2 are involved in the expression of cell cycle regulators including cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. In addition, correlation of the down-regulation of PER1 and PER2 with development of many cancer types has been revealed. In this review, we focused on the molecular function of PER1 and PER2 in the circadian clock network and the transcriptional and translational targets of PER1 and PER2 involved in cell cycle and tumorigenesis. Moreover, we provide information suggesting that PER1 and PER2 could be promising therapeutic targets for cancer therapies and serve as potential prognostic markers for certain types of human cancers.

• Journal of Integrative Natural Science
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• v.16 no.3
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• pp.75-80
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• 2023

Bipolar disorder is a mental illness characterized by extreme mood and behavioral swings, such as highs of euphoria and lows of depression. It is a socially significant disorder in which people with the disorder experience intense mood swings and, for those with severe bipolar disorder, it is even difficult leading a normal life. High stress levels in people with mental illness can lead to neuroendocrine disruption, and it is strongly linked to aging. When the neuroendocrine system becomes vulnerable to these mental illnesses and stress, it is likely to accelerate aging. And it's the epigenetic clock that can measure the extent of this accelerated aging. The Epi clock, a pan tissue clock, measures aging through DNA methylation, and the degree of methylation is modified and changed by environmental conditions in the body. Therefore we wanted to check the changes in the epigenetic age of the patients with bipolar disorder. While we found no significant differences in epigenetic age, we did confirm the possibility that people with bipolar disorder have different methylation than normal people. We also found that the EPIC array data fit better on the Epi clock than on the Horvath clock with age-accelerated data from normal people.

• Development and Reproduction
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• v.7 no.1
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• pp.1-7
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• 2003

Most animals, including human beings, live in a cyclic pattern of lift that is influenced by the ambient changes of environment. The regular changes occurred by rotation of the Earth itself its revolving around the Sun, and the local environment, are reflected by the distinct behavior in the living organisms. These regular changes of environment have been imprinted into the genes within the living organisms through the evolutionary process over a long period of time. The genes are expressed by rhythms during the process of fetal development followed by growth. The environmental modifications ultimately are settled in genes, serving as a biological clock that is located putatively in the hypothalamus. Thus the biological clock governs a large number of rhythms and affects the time of birth and death lift expectancy, behavior, physiology, cell division, biochemical reaction, etc. The rhythms are readjusted to the changes of environmental cues. The biological clock has the great advantage of predicting and preparing the regular changes of environment.

• Molecules and Cells
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• v.42 no.4
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• pp.301-312
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• 2019

Post-transcriptional regulation underlies the circadian control of gene expression and animal behaviors. However, the role of mRNA surveillance via the nonsense-mediated mRNA decay (NMD) pathway in circadian rhythms remains elusive. Here, we report that Drosophila NMD pathway acts in a subset of circadian pacemaker neurons to maintain robust 24 h rhythms of free-running locomotor activity. RNA interference-mediated depletion of key NMD factors in timeless-expressing clock cells decreased the amplitude of circadian locomotor behaviors. Transgenic manipulation of the NMD pathway in clock neurons expressing a neuropeptide PIGMENT-DISPERSING FACTOR (PDF) was sufficient to dampen or lengthen free-running locomotor rhythms. Confocal imaging of a transgenic NMD reporter revealed that arrhythmic Clock mutants exhibited stronger NMD activity in PDF-expressing neurons than wild-type. We further found that hypomorphic mutations in Suppressor with morphogenetic effect on genitalia 5 (Smg5) or Smg6 impaired circadian behaviors. These NMD mutants normally developed PDF-expressing clock neurons and displayed daily oscillations in the transcript levels of core clock genes. By contrast, the loss of Smg5 or Smg6 function affected the relative transcript levels of cAMP response element-binding protein B (CrebB) in an isoform-specific manner. Moreover, the overexpression of a transcriptional repressor form of CrebB rescued free-running locomotor rhythms in Smg5-depleted flies. These data demonstrate that CrebB is a rate-limiting substrate of the genetic NMD pathway important for the behavioral output of circadian clocks in Drosophila.

• Molecules and Cells
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• v.27 no.5
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• pp.497-502
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• 2009

In mouse embryos, somite formation occurs every two hours, and this periodic event is regulated by a biological clock called the segmentation clock, which involves cyclic expression of the basic helix-loop-helix gene Hes7. Hes7 expression oscillates by negative feedback and is cooperatively regulated by Fgf and Notch signaling. Both loss of expression and sustained expression of Hes7 result in severe somite fusion, suggesting that Hes7 oscillation is required for proper somite segmentation. Expression of a related gene, Hes1, also oscillates by negative feedback with a period of about two hours in many cell types such as neural progenitor cells. Hes1 is required for maintenance of neural progenitor cells, but persistent Hes1 expression inhibits proliferation and differentiation of these cells, suggesting that Hes1 oscillation is required for their proper activities. Hes1 oscillation regulates cyclic expression of the proneural gene Neurogenin2 (Ngn2) and the Notch ligand Delta1, which in turn lead to maintenance of neural progenitor cells by mutual activation of Notch signaling. Taken together, these results suggest that oscillatory expression with short periods (ultradian oscillation) plays an important role in many biological events.

• Journal of Korean Biological Nursing Science
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• v.18 no.4
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• pp.305-317
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• 2016

Purpose: Recent studies demonstrated disruption of the circadian clock gene is associated with the development of obesity and metabolic syndrome. Obesity is often caused by the high calorie intake, In addition, the chronic stress tends to contribute to the increased risk for obesity. To evaluate the molecular mechanisms, we examined the expression of circadian clock genes in high fat diet-induced mice models with the chronic stress. Methods: C57BL/6J mice were fed with a 45% or 60% high fat diet for 8 weeks. Daily immobilization stress was applied to mice fed with a 45% high fat for 16 weeks. We compared body weight, food consumption, hormone levels and metabolic variables in blood. mRNA expression levels of metabolic and circadian clock genes in both fat and liver were determined by quantitative RT-PCR. Results: The higher fat content induced more severe hyperglycemia, hyperlipidemia and hyperinsulinemia, and these results correlated with their relevant gene expressions in fat and liver tissues. Chronic stress had only minimal effects on metabolic variables, but it altered the expression patterns of metabolic and circadian clock genes. Conclusion: These results suggest that the fat metabolism regulates the function of the circadian clock genes in peripheral tissues, and stress hormones may contribute to its regulation.