• Genomics & Informatics
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• 제18권4호
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• pp.38.1-38.9
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• 2020

Chronotype is an important moderator of psychiatric illnesses, which seems to be controlled in some part by genetic factors. Clock genes are the most relevant genes for chronotype. In addition to the roles of individual genes, gene-gene interactions of clock genes substantially contribute to chronotype. We investigated genetic associations and gene-gene interactions of the clock genes BHLHB2, CLOCK, CSNK1E, NR1D1, PER1, PER2, PER3, and TIMELESS for chronotype in 1,293 healthy Korean individuals. Regression analysis was conducted to find associations between single nucleotide polymorphism (SNP) and chronotype. For gene-gene interaction analyses, the quantitative multifactor dimensionality reduction (QMDR) method, a nonparametric model-free method for quantitative phenotypes, were performed. No individual SNP or haplotype showed a significant association with chronotype by both regression analysis and single-locus model of QMDR. QMDR analysis identified NR1D1 rs2314339 and TIMELESS rs4630333 as the best SNP pairs among two-locus interaction models associated with chronotype (cross-validation consistency [CVC] = 8/10, p = 0.041). For the three-locus interaction model, the SNP combination of NR1D1 rs2314339, TIMELESS rs4630333, and PER3 rs228669 showed the best results (CVC = 4/10, p < 0.001). However, because the mean differences between genotype combinations were minor, the clinical roles of clock gene interactions are unlikely to be critical.

• 한국동물번식학회:학술대회논문집
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• 한국동물번식학회 2004년도 춘계학술발표대회
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• pp.261-261
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• 2004

Circadian rhythms, which measure time about 24 hours, are generated by one of the most ubiquitous and well investigated timing system. More recently, circadian clock gene expression has been reported in various peripheral tissues. If a circadian clock is functioning in the testis, expression of clock genes should be observed in this tissue. To resolve this issue, we examined the expression of circadian clock genes in the testis. (omitted)

• Animal cells and systems
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• 제9권3호
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• pp.153-160
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• 2005

Most living organisms exhibit the circadian rhythm in their physiology and behavior. Recent identification of several clock genes in mammals has led to the molecular understanding of how these components generate and maintain the circadian rhythm. Many reports have implicated the photic induction of either mPer1 or mPer2 in the hypothalamic region called the suprachiasmatic nucleus (SCN) to phase shift the brain clock. It is now established that peripheral tissues other than the brain also express these clock genes and that the clock machinery in these tissues work in a similar way to the SCN clock. To determine the role of the two canonical clock genes, mPer1 and mPer2, in the peripheral clock shift, stable HEK293EcR cell lines that can be induced and stably express these proteins were prepared. By regulating the expression of these proteins, it could be shown that induction of the clock genes, either mPer1 or mPer2 alone is not sufficient to cause clock phase shifting in these cells. Our real-time PCR analysis on these cells indicates that the induction of mPER proteins dampens the expression of the clock-specific transcription factor mBmal1. Altogether, our present data suggest that mPer1 and mPer2 may not function in clock shift or take part in differential roles on the peripheral circadian clock.

• Molecules and Cells
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• 제22권3호
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• pp.285-290
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• 2006

The light sensing system in the eye directly affects the circadian oscillator in the mammalian suprachiasmatic nucleus (SCN). To investigate this relationship in the rat, we examined the circadian expression of clock genes in the SCN and eye tissue during a 24 h day/night cycle. In the SCN, rPer1 and rPer2 mRNAs were expressed in a clear circadian rhythm like rCry1 and rCry2 mRNAs, whereas the level of BMAL1 and CLOCK mRNAs decreased during the day and increased during the night with a relatively low amplitude. It seems that the clock genes of the SCN may function in response to a master clock oscillation in the rat. In the eye, the rCry1 and rCry2 were expressed in a circadian rhythm with an increase during subjective day and a decrease during subjective night. However, the expression of Opn4 mRNA did not exhibit a clear circadian pattern, although its expression was higher in daytime than at night. This suggests that cryptochromes located in the eye, rather than melanopsin, are the major photoreceptive system for synchronizing the circadian rhythm of the SCN in the rat.

• 생명과학회지
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• 제27권10호
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• pp.1225-1231
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• 2017

암을 포함한 다양한 인간의 질병 발생이 circadian clock 유전자의 변형된 발현 양상과 깊은 연관관계를 나타내고 있다. 세포 주기와 세포 성장은 circadian rhythm과 연결되어 있으며, 이를 조절하는 clock 유전자의 비정상적인 발현은 결국 종양 발생과 암의 발달을 유발하게 된다. Circadian clock에 관한 분자적 기전은 다수의 clock activator와 clock repressor의 통합적인 조절에 따른 전사 및 번역이 포함된 음성피드백 고리로 구성되어 있다. 이러한 circadian rhythm의 자동조절 기전에 의해 전체 유전체의 약 10~15%가 전사 수준에서 영향받는 것으로 나타났다. 많은 clock 유전자들 중, Period 1 (Per1)과 Period 2 (Per2)는 clock repressor 유전자로 정상적인 생리적 리듬을 조절하는 것에 기여한다. PER1과 PER2는 cyclin, CDK, CKI를 포함하는 세포 주기 조절자의 발현에 관여함이 밝혀졌으며, 다양한 암에서 PER1과 PER2의 발현 감소가 보고되었다. 따라서, 본 논문에서는 PER1과 PER2의 circadian rhythm에서의 분자적 기능과 종양 발생과 관련된 PER1과 PER2의 하위 표적인자에 대해 살펴보고, 암 치료를 위한 새로운 치료 표적과 암의 예후를 예측하기 위한 분자 지표로써의 PER1과 PER2의 가능성에 대해 서술하고자 한다.

• Molecules and Cells
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• 제28권2호
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• pp.75-80
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• 2009

The cyclic environmental conditions brought about by the 24 h rotation of the earth have allowed the evolution of endogenous circadian clocks that control the temporal alignment of behaviour and physiology, including the uptake and processing of nutrients. Both metabolic and circadian regulatory systems are built upon a complex feedback network connecting centres of the central nervous system and different peripheral tissues. Emerging evidence suggests that circadian clock function is closely linked to metabolic homeostasis and that rhythm disruption can contribute to the development of metabolic disease. At the same time, metabolic processes feed back into the circadian clock, affecting clock gene expression and timing of behaviour. In this review, we summarize the experimental evidence for this bimodal interaction, with a focus on the molecular mechanisms mediating this exchange, and outline the implications for clock-based and metabolic diseases.

• 한국발생생물학회지:발생과생식
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• 제8권1호
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• pp.57-64
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• 2004

본 연구는 생쥐의 난소 및 정소 조직에서 발달 단계에 따라 나타나는 일주기성 clock유전자의 발현과 단백질의 발현 양상을 알아보고자 하였다. 생쥐의 난소 및 정소에서 일주기성 변화와 연관된 유전자(Period1(Per1), Period2(Per2), Period3(Per3), Cryptochromel(Cry1), Cryptochrome2 (Cry2), Clock, Bmall)와 시교차 상핵에서 분비되어 표적 조직 또는 기관으로 전달되는 물질로 알려진 Prokineticin (Prok2)에 대 한 수용체들 (Prok1r과 Prok2r), PERI 단백질의 발현 양상을 발달 단계에 따라 (post partum day; ppd 1, 7, 10, 21, 35) 확인하였다. 주요 clock 유전자들은 생후 발달 단계에 따라 각각 다양한 발현양상을 보였다. 난소의 경우 많은 난포가 성장을 시작하는 시기인 생후 7일과 10일을 전후하여 발현량이 대부분 증가하는 것을 볼 수 있었으며, 정소의 경우에도 발달 단계에 따라 7일에서 발현이 증가하는 양상을 보였다. 특히 clock유전자들은 생후 7일과 10일에서 상대적으로 높은 발현 양상을 보였다 시교차 상핵에서 분비되어 표적기관으로 분비되는 것으로 알려진 Prok2의 수용체의 경우에도 주요 주기성 유전자들의 발현이 증가하는 것과 같은 시기에 발현이 높아지는 것을 확인할 수 있었고, 생식소 발달 초기에 강하게 발현되나 차후 점진적으로 감소하는 것을 확인할 수 있었다. 또한 PER1의 발현양상을 면역조직화학적 방법으로 확인한 결과, 난포의 각 발달 단계에서 난소 내 정상적인 난포의 과립세포와 난자에서 높게 발현되는 것을 알 수 있었고, 상기의 결과는 Perl 유전자의 발현 양상과 일치함을 확인할 수 있었다 또한 정소 내 Per1 유전자와 PER1 단백질의 발현은 모두 생후 10일과 21일에서 감소하는 경향을 보이나 성적으로 성숙됨에 따라 다시 증가하는 것을 확인할 수 있어, PER1 단백질은 생식소의 발생 단계별로 다양한 발현 양상의 차이를 보이며, 정자와 난자의 정상적인 발달에 밀접한 연관이 있음을 추론할 수 있었다. 본 연구의 결과, 일주기성 clock유전자들 중 특히 Per1이 생식소의 정상 발달에 중요하게 작용할 수 있음을 시사하여 차후 이에 대한 다양한 연구가 진행되어야 할 것으로 생각된다.

• Journal of Korean Biological Nursing Science
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• 제18권4호
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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.

• Molecules and Cells
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• 제22권3호
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• pp.275-284
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• 2006

The molecular components that generate and maintain circadian rhythms of physiology and behavior in mammals are present both in the brain (suprachiasmatic nucleus; SCN) and in peripheral tissues. Examination of mice with targeted disruptions of either mPer1 or mPer2 has shown that these two genes have key roles in the SCN circadian clock. Here we show that loss of the clock gene mPer2 affects forced locomotor performance in mice without altering muscle contractility. A proteomic analysis revealed that the anterior tibialis muscles of the mPer2 knockout mice had higher levels of glycolytic enzymes such as triose phosphate isomerase and enolase than those of either the wild type or mPer1 knockout mice. In addition, the level of expression of HSP90 in the mPer2 mutant mice was also significantly higher than in wildtype mice. These results suggest that the reduced locomotor endurance of the mPer2 knockout mice reflects a greater dependence on anaerobic metabolism under stress conditions, and that the two canonical clock genes, mPer1 and mPer2, play distinct roles in the physiology of skeletal muscle.

• Reproductive and Developmental Biology
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• 제33권3호
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• pp.163-169
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• 2009

Many biological systems are regulated by an intricate set of feedback loops that oscillate with a circadian rhythm of roughly 24 h. This circadian clock mediates an increase in body temperature, heart rate, blood pressure, and cortisol secretion early in the day. Recent studies have shown changes in the amplitude of the circadian clock in the hearts and livers of streptozotocin (STZ)-treated rats. It is therefore important to examine the relationships between circadian clock genes and growth factors and their effects on diabetic phenomena in animal models as well as in human patients. In this study, we sought to determine whether diurnal variation in organ development and the regulation of metabolism, including growth and development during the juvenile period in rats, exists as a mechanism for anticipating and responding to the environment. Also, we examined the relationship between changes in growth factor expression in the liver and clock-controlled protein synthesis and turnover, which are important in cellular growth. Specifically, we assessed the expression patterns of several clock genes, including Per1, Per2, Clock, Bmal1, Cry1 and Cry2 and growth factors such as insulin-like growth factor (IGF)-1 and -2 and transforming growth factor (TGF)-${\beta}1$ in rats with STZ-induced diabetes. Growth factor and clock gene expression in the liver at 1 week post-induction was clearly increased compared to the level in control rats. In contrast, the expression patterns of the genes were similar to those observed after 5 weeks in the STZ-treated rats. The increase in gene expression is likely a compensatory change in response to the obstruction of insulin function during the initial phase of induction. However, as the period of induction was extended, the expression of the compensatory genes decreased to the control level. This is likely the result of decreased insulin secretion due to the destruction of beta cells in the pancreas by STZ.