Period2 3'-UTR and microRNA-24 regulate circadian rhythms by repressing PERIOD2 protein accumulation.

We previously created two PER2::LUCIFERASE (PER2::LUC) circadian reporter knockin mice that differ only in the Per2 3'-UTR region: Per2::Luc, which retains the endogenous Per2 3'-UTR and Per2::LucSV, where the endogenous Per2 3'-UTR was replaced by an SV40 late poly(A) signal. To delineate the in vivo functions of Per2 3'-UTR, we analyzed circadian rhythms of Per2::LucSV mice. Interestingly, Per2::LucSV mice displayed more than threefold stronger amplitude in bioluminescence rhythms than Per2::Luc mice, and also exhibited lengthened free-running periods (∼24.0 h), greater phase delays following light pulse, and enhanced temperature compensation relative to Per2::Luc Analysis of the Per2 3'-UTR sequence revealed that miR-24, and to a lesser degree miR-30, suppressed PER2 protein translation, and the reversal of this inhibition in Per2::LucSV augmented PER2::LUC protein level and oscillatory amplitude. Interestingly, Bmal1 mRNA and protein oscillatory amplitude as well as CRY1 protein oscillation were increased in Per2::LucSV mice, suggesting rhythmic overexpression of PER2 enhances expression of Per2 and other core clock genes. Together, these studies provide important mechanistic insights into the regulatory roles of Per2 3'-UTR, miR-24, and PER2 in Per2 expression and core clock function.

Peripheral Skin Temperature and Circadian Biological Clock in Shift Nurses after a Day off.

The circadian biological clock is essentially based on the light/dark cycle. Some people working with shift schedules cannot adjust their sleep/wake cycle to the light/dark cycle, and this may result in alterations of the circadian biological clock. This study explored the circadian biological clock of shift and daytime nurses using non-invasive methods. Peripheral skin temperature, cortisol and melatonin levels in saliva, and Per2 expression in pubic hair follicle cells were investigated for 24 h after a day off. Significant differences were observed in peripheral skin temperature and cortisol levels between shift and daytime nurses. No differences in melatonin levels were obtained. Per2 maximum values were significantly different between the two groups. Shift nurses exhibited lower circadian variations compared to daytime nurses, and this may indicate an adjustment of the circadian biological clock to continuous shift schedules. Non-invasive procedures, such as peripheral skin temperature measurement, determination of cortisol and melatonin in saliva, and analysis of clock genes in hair follicle cells, may be effective approaches to extensively study the circadian clock in shift workers.

PER2 gene and its association with sleep-related disorders: A review.

The natural circadian rhythm in an individual governs the sleep-wake cycle over 24 h. Disruptions in this internal cycle can lead to major health hazards and sleep disorders. Reports suggest that at least 50 % of people worldwide suffer from sleep-related disorders. An increase in screen time, especially in the wake of the COVID-19 pandemic, is one of the external causative factors for this condition. While many factors govern the circadian clock and its aberrance, the PER2 gene has been strongly linked to chronotypes by many researchers. The current paper provides an extensive examination of key Single Nucleotide Polymorphisms within the PER2 gene and their potential connection to four major types of sleep disorders. This study investigates whether these SNPs play a causative role in sleep disorders or if they are solely associated with these conditions. Additionally, we explore whether these genetic variations exert a lifelong influence on these sleep patterns or if external triggers contribute to the development of sleep disorders. This gene is a crucial regulator of the circadian cycle responsible for the transcription of other clock genes. It regulates a variety of physiological systems such as metabolism, sleep, body temperature, blood pressure, endocrine, immunological, cardiovascular, and renal function. We aim to establish some clarity to the multifaceted nature of this gene, which is often overlooked, and seek to establish the mechanistic role of PER2 gene mutations in sleep disorders. This will improve further understanding, assessment, and treatment of these conditions in future.

[Genes of the circadian rhythm and sleep disorders in an open population of men aged 25-64 years (an epidemiological study under the WHO MONICA-PSYCHOSOCIAL program)]. / Geny tsirkadnogo ritma i narusheniya sna v otkrytoi populyatsii muzhchin 25­64 let (epidemiologicheskoe issledovanie po programme VOZ MONICA-PSYCHOSOCIAL).

OBJECTIVE: To study an effect of polymorphisms of genes encoding circadian rhythm proteins (CLOCK, BMAL1, PER2, NPAS2) on sleep disorders in men aged 25-64 years. MATERIAL AND METHODS: The general examination was carried out according to standard methods included in the WHO MONICA-psychosocial (MOPSY) program. The standard Jenkins questionnaire was used to study sleep disorders. Genotyping of the polymorphisms of CLOCK, BMAL1, PER2, NPAS2 was carried out. RESULTS: Carriers of the C/T genotype of CLOCK rs2412646 were more likely to think that their sleep was «satisfactory¼ or «bad¼. Carriers of the C/T genotype of BMAL1 rs2278749 were more likely to experience disturbing dreams, they woke up tired and exhausted. Carriers of the A/A genotype of PER2 rs934945 were more likely (25%) to wake up two or more times a night, in general, from 4 to 7 times a week. In the population, the C/T and T/T genotypes of NPAS2 rs4851377 were significantly more common in individuals with 7-hour sleep (50% and 53.3%, respectively). CONCLUSION: An association of certain polymorphisms of tCLOCK, BMAL1, PER2, NPAS2 with sleep disorders was found.

Relationship between APOE, PER2, PER3 and OX2R Genetic Variants and Neuropsychiatric Symptoms in Patients with Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the presence of neuropsychiatric or behavioral and psychological symptoms of dementia (BPSD). BPSD have been associated with the APOE_ε4 allele, which is also the major genetic AD risk factor. Although the involvement of some circadian genes and orexin receptors in sleep and behavioral disorders has been studied in some psychiatric pathologies, including AD, there are no studies considering gene-gene interactions. The associations of one variant in PER2, two in PER3, two in OX2R and two in APOE were evaluated in 31 AD patients and 31 cognitively healthy subjects. Genotyping was performed using real-time PCR and capillary electrophoresis from blood samples. The allelic-genotypic frequencies of variants were calculated for the sample study. We explored associations between allelic variants with BPSD in AD patients based on the NPI, PHQ-9 and sleeping disorders questionnaires. Our results showed that the APOE_ε4 allele is an AD risk variant (p = 0.03). The remaining genetic variants did not reveal significant differences between patients and controls. The PER3_rs228697 variant showed a nine-fold increased risk for circadian rhythm sleep-wake disorders in Mexican AD patients, and our gene-gene interaction analysis identified a novel interaction between PERIOD and APOE gene variants. These findings need to be further confirmed in larger samples.

For whom the circadian clock ticks? Investigation of PERIOD and CLOCK gene variants in bipolar disorder.

Clock genes play significant roles in the regulation of circadian rhythms, which are thought to be involved in the pathophysiology of neurodegenerative and psychiatric diseases. We aimed to investigate the association of five gene polymorphisms (PER3 VNTR (rs57875989), PER2 rs2304672, CLOCK rs1801260, CLOCK rs10462028, CLOCK rs11932595) with PCR-based methods as potential risk factors in bipolar disorder (BD). We used a multiple testing methodology in BD patients (n = 121) and healthy control individuals (n = 121) of Turkish descent to analyze the effects of these gene variants both as risk factors for the disorder and for the evaluation of these variants in the patient group with multiple subscales. We evaluated the circadian rhythm disturbances and seasonal variations in mood and behavior in BD patients using the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) and Seasonal Pattern Assessment Questionnaire (SPAQ) to enlighten the possible links between these scores and the studied circadian gene variants. The results of our study revealed significant associations: PER3 VNTR (rs57875989) 5/5 repeat genotype displayed a protective effect against BD when compared with 4/4 repeat genotype. Moreover, patients with PER3 VNTR 5/5 repeat genotype displayed a higher ratio of hypomania. PER2 rs2304672 G allele frequency increased the risk for BD. There was no association in terms of genotype/allele frequency comparisons between patients and controls for CLOCK gene variants. However, significant associations were found in patients in terms of clinical and behavioral patterns such as mean age at disease onset and BRIAN total scores enabling some risk stratifications for patients. Our results indicate the significance of circadian gene variants in BD, which need to be confirmed in different studies with larger samples. Thus, the possible endophenotypes of BD can be enlightened and advanced chronotherapeutics approaches can be manipulated in the future for clinical benefit.

Dual Effect of PER2 C111G Polymorphism on Cognitive Functions across Progression from Subjective Cognitive Decline to Mild Cognitive Impairment.

BACKGROUND: Periodic circadian protein homolog 2 (PER2) has a role in the intracellular signaling pathways of long-term potentiation and has implications for synaptic plasticity. We aimed to assess the association of PER2 C111G polymorphism with cognitive functions in subjective cognitive decline (SCD). METHODS: Forty-five SCD patients were included in this study. All participants underwent extensive neuropsychological investigation, analysis of apolipoprotein E (APOE) and PER2 genotypes, and neuropsychological follow-up every 12 or 24 months for a mean time of 9.87 ± 4.38 years. RESULTS: Nine out of 45 patients (20%) were heterozygous carriers of the PER2 C111G polymorphism (G carriers), while 36 patients (80%) were not carriers of the G allele (G non-carriers). At baseline, G carriers had a higher language composite score compared to G non-carriers. During follow-up, 15 (34.88%) patients progressed to mild cognitive impairment (MCI). In this group, we found a significant interaction between PER2 G allele and follow-up time, as carriers of G allele showed greater worsening of executive function, visual-spatial ability, and language composite scores compared to G non-carriers. CONCLUSIONS: PER2 C111G polymorphism is associated with better language performance in SCD patients. Nevertheless, as patients progress to MCI, G allele carriers showed a greater worsening in cognitive performance compared to G non-carriers. The effect of PER2 C111G polymorphism depends on the global cognitive status of patients.

Dual-Color Single-Cell Imaging of the Suprachiasmatic Nucleus Reveals a Circadian Role in Network Synchrony.

The suprachiasmatic nucleus (SCN) acts as a master pacemaker driving circadian behavior and physiology. Although the SCN is small, it is composed of many cell types, making it difficult to study the roles of particular cells. Here we develop bioluminescent circadian reporter mice that are Cre dependent, allowing the circadian properties of genetically defined populations of cells to be studied in real time. Using a Color-Switch PER2::LUCIFERASE reporter that switches from red PER2::LUCIFERASE to green PER2::LUCIFERASE upon Cre recombination, we assess circadian rhythms in two of the major classes of peptidergic neurons in the SCN: AVP (arginine vasopressin) and VIP (vasoactive intestinal polypeptide). Surprisingly, we find that circadian function in AVP neurons, not VIP neurons, is essential for autonomous network synchrony of the SCN and stability of circadian rhythmicity.

Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2.

Most organisms have adapted to a circadian rhythm that follows a roughly 24-hour cycle, which is modulated by both internal (clock-related genes) and external (environment) factors. In such organisms, the central nervous system (CNS) is influenced by the circadian rhythm of individual cells. Furthermore, the period circadian clock 2 (Per2) gene is an important component of the circadian clock, which modulates the circadian rhythm. Per2 is mainly expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as other brain areas, including the midbrain and forebrain. This indicates that Per2 may affect various neurobiological activities such as sleeping, depression, and addiction. In this review, we focus on the neurobiological functions of Per2, which could help to better understand its roles in the CNS.

Clock gene Per2 as a controller of liver carcinogenesis.

Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine (DEN) exposure according to constitutive Per2 mutation. First, we found that Per2m/m liver displayed profound alterations in proliferation gene expression, including c-Myc derepression, phase-advanced Wee1, and arrhythmic Ccnb1 and K-ras mRNA expressions, as well as deregulated inflammation, through arrhythmic liver IL-6 protein concentration, in the absence of any DEN exposure. These changes could then make Per2m/m mice more prone to subsequently develop liver cancers on DEN. Indeed, primary liver cancers were nearly fourfold as frequent in Per2m/m mice as compared to wild-type (WT), 4 months after DEN exposure. The liver molecular clock was severely disrupted throughout the whole carcinogenesis process, including the initiation stage, i.e. within the initial 17 days on DEN. Per2m/m further exhibited increased c-Myc and Ccnb1 mean 24h expressions, lack of P53 response, and arrhythmic ATM, Wee1 and Ccnb1 expressions. DEN-induced tumor related inflammation was further promoted through increased protein concentrations of liver IL-6 and TNF-α as compared to WT during carcinogenesis initiation. Per2 mutation severely deregulated liver gene or protein expressions related to three cancer hallmarks, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold. Clock gene Per2 acted here as a liver tumor suppressor from initiation to progression.