Circadian clock is an internal autonomous time-keeping system, including central clocks located in the suprachiasmatic nucleus (SCN) and peripheral clocks. The molecular circadian clock consists of a set of interlocking transcriptional-translational feedback loops that take the clock-controlled genes 24 h to oscillate. The core mechanism of molecular circadian clock is that CLOCK/BMAL1 dimer activates the transcription of cryptochromes (CRYs) and Periods (PERs), which act as transcriptional repressors of further CLOCK/BMAL1-mediated transcription. In addition to this basic clock, there is an additional sub-loop of REV-ERBα and RORα regulating the transcription of BMAL1. Approximately 80% protein-coding genes demonstrate significant rhythmicity. The earth rotation is responsible for the generation of the daily circadian rhythms. To coordinate metabolic balance and energy availability, almost all organisms adapt to the rhythm. Studies have shown that circadian clock integrating with metabolic homeostasis increases the efficiency of energy usage and coordinates with different organs in order to adapt to internal physiology and external environment soon. As the central organ of metabolism, the liver performs various physiological activities nearly all controlled by the circadian clock. There are multiple interactive regulation mechanisms between the circadian clock and the regulation of liver metabolism. The misalignment of metabolism with tissue circadian is identified as a high-risk factor of metabolic diseases. This article reviews the recent studies on circadian physiological regulation of liver glucose, lipid and protein metabolism and emphasizes oscillation of mitochondrial function. We also take an outlook for new methods and application of circadian clock research in the future.
CLOCK Proteins ; Circadian Clocks/genetics* ; Circadian Rhythm ; Liver ; Suprachiasmatic Nucleus

Cardiovascular Diseases ; Cardiovascular System ; Circadian Clocks/genetics* ; Circadian Rhythm ; Humans

Mammalian bone is constantly metabolized from the embryonic stage, and the maintenance of bone health depends on the dynamic balance between bone resorption and bone formation, mediated by osteoclasts and osteoblasts. It is widely recognized that circadian clock genes can regulate bone metabolism. In recent years, the regulation of bone metabolism by non-coding RNAs has become a hotspot of research. MicroRNAs can participate in bone catabolism and anabolism by targeting key factors related to bone metabolism, including circadian clock genes. However, research in this field has been conducted only in recent years and the mechanisms involved are not yet well established. Recent studies have focused on how to target circadian clock genes to treat some diseases, such as autoimmune diseases, but few have focused on the co-regulation of circadian clock genes and microRNAs in bone metabolic diseases. Therefore, in this paper we review the progress of research on the co-regulation of bone metabolism by circadian clock genes and microRNAs, aiming to provide new ideas for the prevention and treatment of bone metabolic diseases such as osteoporosis.
Animals ; Circadian Clocks/genetics* ; Circadian Rhythm/genetics* ; Mammals/genetics* ; MicroRNAs/genetics* ; Osteogenesis/genetics* ; Osteoporosis/genetics*

The cyanobacterial circadian clock has three relatively independent parts: the input path, the core oscillator, and the output path. The core oscillator is composed of three clock proteins: KaiA, KaiB, and KaiC. The interactions among these three proteins generate a rhythmic signal and convey the input signals to the output signals to maintain the accuracy and stability of the oscillation of downstream signals. Based on the cyanobacterial circadian clock and the structure, function, and interaction of the clock proteins of the core oscillator, combining the recent results from our laboratory, this review summarized the recent progresses of the molecular mechanism of KaiA in regulating KaiC's enzymatic activity, mediating phase reset of the oscillator, and competing with CikA for the binding site of KaiB.
Bacterial Proteins ; genetics ; metabolism ; Circadian Clocks ; genetics ; Circadian Rhythm Signaling Peptides and Proteins ; metabolism ; Cyanobacteria ; genetics ; Enzyme Activation ; genetics

Circadian clocks are the internal time-keeping mechanisms for organisms to synchronize their cellular and physiological processes to the daily light/dark cycles. The molecular mechanisms underlying circadian clocks are remarkably similar in eukaryotes. Neurospora crassa, a filamentous fungus, is one of the best understood model organisms for circadian research. In recent years, accumulating data have revealed complex regulation in the Neurospora circadian clock at transcriptional, posttranscriptional, post-translational and epigenetic levels. Here we review the recent progress towards our understanding of the molecular mechanism of the Neurospora circadian oscillator. These advances have provided novel insights and furthered our understanding of the mechanism of eukaryotic circadian clocks.
Circadian Clocks ; Epigenomics ; Neurospora ; genetics ; metabolism ; physiology ; Neurospora crassa ; genetics ; metabolism ; physiology

Circadian Clocks/genetics* ; Reactive Oxygen Species ; Methionine ; Gastrointestinal Microbiome ; Gastrointestinal Tract ; Racemethionine ; Gene Expression

Light is one of the key environmental signals regulating plant growth and development. Therefore, understanding the mechanisms by which light controls plant development has long been of great interest to plant biologists. Traditional genetic and molecular approaches have successfully identified key regulatory factors in light signaling, but recent genomic studies have revealed massive reprogramming of plant transcriptomes by light, identified binding sites across the entire genome of several pivotal transcription factors in light signaling, and discovered the involvement of epigenetic regulation in light-regulated gene expression. This review summarizes the key genomic work conducted in the last decade which provides new insights into light control of plant development.
Circadian Clocks ; physiology ; Epigenesis, Genetic ; Gene Expression Regulation, Plant ; Genome, Plant ; Genomics ; Light ; Plant Development ; Plants ; genetics ; metabolism ; Signal Transduction ; Transcription Factors ; physiology ; Transcriptome ; Ultraviolet Rays

OBJECTIVETo determine the regulatory effects of the circadian clock gene Per1 on cell cycle-related genes and its influence on the proliferation, apoptosis, cycle, and tumorigenicity in vivo of human oral squamous cell carcinoma SCC15 cells.

METHODSThree groups of the short hairpin RNA (shRNA) of lentivirus recombinant plasmids were designed against the RNA of Per1 and then transfected to the SCC15 cells. The optimum interference group was screened through Western blot and quantitative real-time PCR (qRT-PCR) and assigned as the experimental group. The transfected lentivirus plasmid without an interference effect on any gene was set as the control group (Control-shRNA). Untreated SCC15 cells were set as the blank group. The mRNA expressions of cell cycle-related genes, namely, Per1, p53, Cyclin D1, Cyclin E, Cyclin A2, Cyclin B1, CDK1, CDK2, CDK4, CDK6, p16, p21, Wee1, cdc25, E2F, and Rbl1 in each group were detected through qRT-PCR. The cell proliferation, apoptosis, and cell cycle distribution in each group were evaluated through flow cytometry. The cells of the experimental group and the blank group were subcutaneously inoculated in nude mice to observe tumorigenesis.

RESULTSThree groups of Per1-shRNA lentivirus plasmids were constructed successfully. Among the groups, the Per1-shRNA- I group exhibited the highest interference effect, as indicated by qRT-PCR and Western blot analysis. As such, this group was set as the experimental group. The mRNA expression levels of CyclinD1, CyclinE, CyclinB1, CDK1, and Wee1 gene in the Per1-shRNA-I group were significantly higher than those in the Control-shRNA group and the SCC15 group (P < 0.05). By contrast, the mRNA expression levels of p53, Cyclin A2, p16, p21, and cdc25 in the Per1-shRNA-I group were significantly lower than those in the Control-shRNA group and the SCC15 group (P < 0.05). The mRNA expression levels of each gene between the Control-sLRNA group and the SCC15 group did not significantly differ (P > 0.05). The mRNA expression levels of CDK2, CDK4, CDK6, E2F, and Rb1 did not significantly differed in the three groups (P > 0.05). The proliferation index of the Perl-shRNA-I group was significantly higher than those of the Control-shRNA group and the SCC15 group (P < 0.05). The apoptosis index of the Per1-shRNA-I group was significantly lower than those of the Control-shRNA group and the SCC15 group (P < 0.05). The number of S-phase cells in the Per1-shRNA-I group was significantly lower than those of S-phase cells in the Control-shRNA group and the SCC15 group (P < 0.05). The number of G2/M-phase cells in the Per1-shRNA-I group was significantly higher than those of G2/M-phase cells in the Control-shRNA group and the SCC15 group (P < 0.05). Conversely, the proliferation index, apoptotic index, and cell cycle distribution of the cells in the Control-shRNA group did not significantly differ from those of the SCC15 group (P > 0.05). The tumorigenic ability in vivo was significantly enhanced in the Per1-shRNA-I group (P < 0.05).

CONCLUSIONPer1 is an important tumor suppressor gene. Per1 can regulate a large number of downstream cell cycle-related genes. The alteration of its expression can affect cell cycle progression, proliferation, apoptosis imbalance, and tumorigenic ability in vivo. Further studies on Per1 may elucidate cancer development and provide novel effective molecular targets for cancer treatment.

Animals ; Apoptosis ; Carcinoma, Squamous Cell ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; Circadian Clocks ; genetics ; Cyclin D1 ; Humans ; Mice ; Mice, Nude ; Mouth Neoplasms ; Period Circadian Proteins ; genetics ; Plasmids ; RNA, Small Interfering ; Real-Time Polymerase Chain Reaction ; Transfection

Circadian clocks are the endogenous oscillators that harmonize a variety of physiological processes within the body. Although many urinary functions exhibit clear daily or circadian variation in diurnal humans and nocturnal rodents, the precise mechanisms of these variations are as yet unclear. In the present study, we demonstrate that Per2 promoter activity clearly oscillates in neonate and adult bladders cultured ex vivo from Per2::Luc knock-in mice. In subsequent experiments, we show that multiple local oscillators are operating in all the bladder tissues (detrusor, sphincter and urothelim) and the lumbar spinal cord (L4-5) but not in the pontine micturition center or the ventrolateral periaqueductal gray of the brain. Accordingly, the water intake and urine volume exhibited daily and circadian variations in young adult wild-type mice but not in Per1-/- Per2-/- mice, suggesting a functional clock-dependent nature of the micturition rhythm. Particularly in PDK mice, the water intake and urinary excretion displayed an arrhythmic pattern under constant darkness, and the amount of water consumed and excreted significantly increased compared with those of WT mice. These results suggest that local circadian clocks reside in three types of bladder tissue and the lumbar spinal cord and may have important roles in the circadian control of micturition function.
Animals ; *Circadian Clocks ; Drinking ; Mice ; Organ Specificity ; Periaqueductal Gray/metabolism/physiology ; Period Circadian Proteins/genetics/*metabolism ; Pons/metabolism/physiology ; Spinal Cord/*metabolism/physiology ; Urinary Bladder/innervation/metabolism/*physiology ; Urination

Sleep deprivation (SD) has many deleterious health effects and occurs in more than 70% of pregnant women. However, the changes in sex hormones and relevant mechanisms after SD have not been well clarified. The aim of the present study was to explore the effects of SD on the secretion of sex hormones and the underlying mechanisms. Twelve pregnant Wistar rats were divided into control (CON, n = 6) and SD (n = 6) groups. Pregnant rats in the SD group were deprived of sleep for 18 h, and allowed free rest for 6 h, and then the above procedures were repeated until delivery. The CON group lived in a 12 h light/dark light cycle environment. Estradiol (E2) and progesterone (P4) levels were detected by enzyme-linked immunosorbent assay (ELISA), and the expression of circadian clock genes, Bmal1, Clock and Per2, in hypothalamus and pituitary gland tissues were evaluated by immunohistochemistry (IHC) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The PI3K and Akt phosphorylation levels in the hypothalamic and pituitary tissues were determined by Western blot. The results showed that, compared with the CON group, the SD group exhibited significantly reduced serum E2 and P4 levels, down-regulated Bmal1, Clock and Per2 expression, as well as decreased phosphorylation levels of PI3K and Akt. But there was no significant difference of the total PI3K and Akt protein expression levels between the two groups. These results suggest that SD might affect the expression of the circadian clock genes in the hypothalamus and pituitary via PI3K/Akt pathway, and subsequently regulate the secretion of sex hormones in the pregnant rats, which hints the important roles of SD-induced changes of serum sex hormone levels in the pregnant rats.
ARNTL Transcription Factors/metabolism* ; Animals ; Circadian Clocks/physiology* ; Circadian Rhythm/genetics* ; Female ; Gene Expression Regulation/genetics* ; Gonadal Steroid Hormones/metabolism* ; Hypothalamus/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Pituitary Gland/metabolism* ; Pregnancy ; Progesterone ; Proto-Oncogene Proteins c-akt/metabolism* ; Rats ; Rats, Wistar ; Signal Transduction ; Sleep Deprivation/metabolism*