Human clock genes

Rhythmic variations in physiological and behavioural processes are mediated by both endogenous and exogenous factors. Endogenous factors include self-sustaining biological pacemakers or clocks which in the absence of strong external influences self-sustain periodic rhythms in such diverse physiological and psychological processes as core body temperature, food intake, cognitive performance and mood. Clocks with endogenous periods near or at 24 h (called circadian clocks from the Latin, circa dies, meaning about one day) have been documented from prokaryotes to single cell eukaryotes to multi-cellular, complex animals such as flies, rodents and humans. Over the past few years, a revolution in the understanding of the molecular basis of these clocks has led to the identification of a number of core clock genes and their proteins, and the development of elegant feedback models to explain the molecular gears of circadian clocks. At least eight human orthologs of mouse core clock genes have been identified, and polymorphisms in two of these, hClock and hPer2, have been implicated in human sleep disorders. Remarkably, knowledge of these core clock genes and the development of sophisticated reporter systems to monitor clock gene promoter activity have led to the astonishing observation that our body is actually composed of millions of cellular clocks and oscillators whose co-ordinated activity gives rise to pronounced daily, monthly, and seasonal rhythms in physiology and behaviour. An idea that is gaining favour is that our physical and mental well-being is probably determined by the appropriate phasing of these millions of cellular clocks with recurring, meaningful events in the environment.     

Cross-talk between the circadian clock and the cell cycle in cancer

Abstract

The circadian clock is an endogenous timekeeper system that controls the daily rhythms of a variety of physiological processes. Accumulating evidence indicates that genetic changes or unhealthy lifestyle can lead to a disruption of circadian homeostasis, which is a risk factor for severe dysfunctions and pathologies including cancer. Cell cycle, proliferation, and cell death are closely intertwined with the circadian clock, and thus disruption of circadian rhythms appears to be linked to cancer development and progression. At the molecular level, the cell cycle machinery and the circadian clocks are controlled by similar mechanisms, including feedback loops of genes and protein products that display periodic activation and repression. Here, we review the circadian rhythmicity of genes associated with the cell cycle, proliferation, and apoptosis, and we highlight the potential connection between these processes, the circadian clock, and neoplastic transformations. Understanding these interconnections might have potential implications for the prevention and therapy of malignant diseases.     

Circadian rhythms, sleep, and metabolism

The discovery of the genetic basis for circadian rhythms has expanded our knowledge of the temporal organization of behavior and physiology. The observations that the circadian gene network is present in most living organisms from eubacteria to humans, that most cells and tissues express autonomous clocks, and that disruption of clock genes results in metabolic dysregulation have revealed interactions between metabolism and circadian rhythms at neural, molecular, and cellular levels. A major challenge remains in understanding the interplay between brain and peripheral clocks and in determining how these interactions promote energy homeostasis across the sleep-wake cycle. In this Review, we evaluate how investigation of molecular timing may create new opportunities to understand and develop therapies for obesity and diabetes.     

Chronological nutrition and prevention of lifestyle-related diseases

Lifestyle controls the circadian rhythms produced by clock genes and affects telomere length that regulates healthspan. Biological clocks are classified into oscillatory (clock genes) and hourglass clocks (telomeres). Clock genes align behavioral and biochemical processes with the day/night cycle. Telomeres, the repeated series of DNA sequences that cap the ends of chromosomes, become shorter during cell division. Shortened telomeres have been documented in various pathological states in lifestyle-related diseases, such as atherosclerosis and diabetes. Human activity is driven by NADH and ATP produced from nutrients, and the resulting NAD and AMP play a predominant role in energy regulation. Caloric restriction and proper exercise increase both AMP and NAD, and extend the healthspan. SIRT1, the NAD-dependent deacetylase, attenuates telomere shortening, while PGC-1alpha, a master modulator of gene expression, is phosphorylated by AMP kinase and deacetylated by SIRT1. Prevention of lifestyle related diseases by chronological nutrition is described based on these mechanisms.     

The circadian clock in mammals

The basic physiological and anatomical basis for circadian rhythms in mammalian behaviour and physiology is introduced. The pathways involved in photic entrainment of the circadian clock are discussed in relation of new findings that identify the molecules that are involved in signalling between the environment and the clock. The molecular basis of endogenous cycles is described in the mouse, and compared to the mechanism that is present in the fly. Finally we speculate on the relationship between circadian physiology and pain.     

The circadian clock in mammals

The basic physiological and anatomical basis for circadian rhythms in mammalian behaviour and physiology is introduced. The pathways involved in photic entrainment of the circadian clock are discussed in relation of new findings that identify the molecules that are involved in signalling between the environment and the clock. The molecular basis of endogenous cycles is described in the mouse, and compared to the mechanism that is present in the fly. Finally we speculate on the relationship between circadian physiology and pain.     

The circadian clock in mammals

The basic physiological and anatomical basis for circadian rhythms in mammalian behaviour and physiology is introduced. The pathways involved in photic entrainment of the circadian clock are discussed in relation of new findings that identify the molecules that are involved in signalling between the environment and the clock. The molecular basis of endogenous cycles is described in the mouse, and compared to the mechanism that is present in the fly. Finally we speculate on the relationship between circadian physiology and pain.     

Interconnections between circadian clocks and metabolism

Circadian rhythms evolved through adaptation to daily light/dark changes in the environment; they are believed to be regulated by the core circadian clock interlocking feedback loop. Recent studies indicate that each core component executes general and specific functions in metabolism. Here, we review the current understanding of the role of these core circadian clock genes in the regulation of metabolism using various genetically modified animal models. Additionally, emerging evidence shows that exposure to environmental stimuli, such as artificial light, unbalanced diet, mistimed eating, and exercise, remodels the circadian physiological processes and causes metabolic disorders. This Review summarizes the reciprocal regulation between the circadian clock and metabolism, highlights remaining gaps in knowledge about the regulation of circadian rhythms and metabolism, and examines potential applications to human health and disease.

To adapt to daily environmental changes caused by our Earth’s rotation, most organisms on the planet evolved near-24-hour cycles of behavioral, physiological, and metabolic rhythms (1). In addition to the entrained environmental stimuli, the internal timekeeping system of the circadian clock has evolved to anticipate external changes (2, 3). These conserved rhythms synchronize internal biological and behavioral processes to the external temporal environment, presumably providing organisms with selective advantages for survival. However, over the past century, modern industrialized society has profoundly changed our external environment (4). For example, the boundaries between day and night have been blurred by electric light and travel across different time zones. Disrupted circadian rhythms are highly associated with metabolic disorders (5). Conversely, obesity induced by overeating or overnutritional environment leads to circadian remodeling (6, 7). Understanding the reciprocal regulation of circadian rhythm and metabolism may provide mechanistic insights into circadian physiology and advance new chronotherapy approaches and therapeutic targets for metabolic disorders.     

Circadian rhythm abnormality and hypertension

In our consumer-oriented society, poor sleep patterns and hectic lifestyle are detrimental to harmonious physiological and metabolic body systems, with severe impact on public health. Circadian rhythms generated by a trillion peripheral cellular clocks throughout the body, governing most aspects of human physiology and behavior, are threatened to be compromised. We recently reported that arrhythmic mice lacking the clock genes Cry1 and Cry2(Cry-null mice) show salt-sensitive hypertension due to abnormally high synthesis of the mineralocorticoid aldosterone in the zoma glomerulosa of the adrenal gland. The clock-controlled enzyme, a new type 3beta-hydroxyl-steroid dehydrogenase, is claimed to be a possible cause of hypertension.     

Extracellular electron transfer mediated by a cytocompatible redox polymer to study the crosstalk among the mammalian circadian clock,cellular metabolism,and cellular redox state

The circadian clock is an endogenous biological timekeeping system that controls various physiological and cellular processes with a 24 h rhythm. The crosstalk among the circadian clock, cellular metabolism, and cellular redox state has attracted much attention. To elucidate this crosstalk, chemical compounds have been used to perturb cellular metabolism and the redox state. However, an electron mediator that facilitates extracellular electron transfer (EET) has not been used to study the mammalian circadian clock due to potential cytotoxic effects of the mediator. Here, we report evidence that a cytocompatible redox polymer pMFc (2-methacryloyloxyethyl phosphorylcholine-co-vinyl ferrocene) can be used as the mediator to study the mammalian circadian clock. EET mediated by oxidized pMFc (ox-pMFc) extracted intracellular electrons from human U2OS cells, resulting in a longer circadian period. Analyses of the metabolome and intracellular redox species imply that ox-pMFc receives an electron from glutathione, thereby inducing pentose phosphate pathway activation. These results suggest novel crosstalk among the circadian clock, metabolism, and redox state. We anticipate that EET mediated by a redox cytocompatible polymer will provide new insights into the mammalian circadian clock system, which may lead to the development of new treatments for circadian clock disorders.

Cytocompatible redox polymer pMFc altered the cellular redox state and metabolism, resulting in a longer circadian period.     

生物节律在恶性肿瘤中的改变及作用

生物节律对机体的生理、代谢和行为具有广泛而重要的调控作用。生物节律的形成是生命体在进化过程中与地球环境相适应的结果，由此形成以地球自转为周期的自主振荡模式。目前已在多种正常细胞中发现由生物节律基因调控的关键基因转录和表达，而这种调控也在肿瘤细胞的形成和进展中起到关键作用。本文总结了关于生物节律与恶性肿瘤发生、发展进程之间相互联系和相关分子机制的研究进展，为基于生物节律的个性化、精准化肿瘤治疗策略的研究提供参考。     

Causal involvement of mammalian-type cryptochrome in the circadian cuticle deposition rhythm in the bean bug Riptortus pedestris

Mammalian-type CRYPTOCHROME (CRY-m) is considered to be a core repressive component of the circadian clock in various insect species. However, this role is based only on the molecular function of CRY-m in cultured cells and it therefore remains unknown whether CRY-m is indispensable for governing physiological rhythms at the organismal level. In the present study, we show that RNA interference (RNAi) targeting of cry-m in the bean bug Riptortus pedestris disrupts the circadian clock governing the cuticle deposition rhythm and results in the generation of a single cuticle layer. Furthermore, period expression was induced in cry-m RNAi insects. These results verified that CRY-m functions as a negative regulator in the circadian clock that generates physiological rhythm at the organismal level.