RESUMO
Delayed sleep phase disorder and advanced sleep phase disorder cause disruption of the circadian clock and present with extreme morning/evening chronotype with unclear role of the genetic etiology, especially for delayed sleep phase disorder. To assess if genotyping can aid in clinical diagnosis, we examined the presence of genetic variants in circadian clock genes previously linked to both sleep disorders in Slovenian patient cohort. Based on Morning-evening questionnaire, we found 15 patients with extreme chronotypes, 13 evening and 2 morning, and 28 controls. Sanger sequencing was used to determine the presence of carefully selected candidate SNPs in regions of the CSNK1D, PER2/3 and CRY1 genes. In a patient with an extreme morning chronotype and a family history of circadian sleep disorder we identified two heterozygous missense variants in PER3 gene, c.1243C>G (NM_001377275.1 (p.Pro415Ala)) and c.1250A>G (NM_001377275.1 (p.His417Arg)). The variants were significantly linked to Advanced sleep phase disorder and were also found in proband's father with extreme morningness. Additionally, a rare SNP was found in PER2 gene in a patient with clinical picture of Delayed sleep phase disorder. The novel variant in PER2 (NM_022817.3):c.1901-218 G>T was found in proband's parent with eveningness, indicating an autosomal dominant inheritance. We identified a family with autosomal dominant inheritance of two PER3 heterozygous variants that can be linked to Advanced sleep phase disorder. We revealed also a rare hereditary form of Delayed sleep phase disorder with a new PER2 variant with autosomal dominant inheritance, shedding the light into the genetic causality.
Assuntos
Relógios Circadianos , Proteínas Circadianas Period , Polimorfismo de Nucleotídeo Único , Transtornos do Sono do Ritmo Circadiano , Humanos , Proteínas Circadianas Period/genética , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Transtornos do Sono do Ritmo Circadiano/genética , Relógios Circadianos/genética , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Predisposição Genética para Doença , Eslovênia , Linhagem , Sono/genética , Sono/fisiologia , Adulto JovemAssuntos
Proteínas CLOCK , Receptores Citoplasmáticos e Nucleares , Proteínas Repressoras , Transtornos do Sono do Ritmo Circadiano , Humanos , Ritmo Circadiano , População do Leste Asiático , Melatonina , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Sono , Transtornos do Sono do Ritmo Circadiano/genética , Proteínas CLOCK/genéticaRESUMO
Protein kinase Cα (PKCα/PRKCA) is a crucial regulator of circadian rhythm and is associated with human mental illnesses such as autism spectrum disorders and schizophrenia. However, the roles of PRKCA in modulating animal social behavior and the underlying mechanisms remain to be explored. Here we report the generation and characterization of prkcaa-deficient zebrafish (Danio rerio). The results of behavioral tests indicate that a deficiency in Prkcaa led to anxiety-like behavior and impaired social preference in zebrafish. RNA-sequencing analyses revealed the significant effects of the prkcaa mutation on the expression of the morning-preferring circadian genes. The representatives are the immediate early genes, including egr2a, egr4, fosaa, fosab and npas4a. The downregulation of these genes at night was attenuated by Prkcaa dysfunction. Consistently, the mutants demonstrated reversed day-night locomotor rhythm, which are more active at night than in the morning. Our data show the roles of PRKCA in regulating animal social interactions and link the social behavior defects with a disturbed circadian rhythm.
Assuntos
Comportamento Animal , Ritmo Circadiano , Proteína Quinase C-alfa , Comportamento Social , Peixe-Zebra , Animais , Humanos , Ansiedade , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Fatores de Transcrição de Resposta de Crescimento Precoce , Transtornos do Sono do Ritmo Circadiano/genética , Peixe-Zebra/genética , Peixe-Zebra/fisiologia , Proteína Quinase C-alfa/genética , Proteína Quinase C-alfa/metabolismoRESUMO
Alzheimer's disease (AD) patients exhibit sleep and circadian disturbances prior to the onset of cognitive decline, and these disruptions worsen with disease severity. However, the molecular mechanisms behind sleep and circadian disruptions in AD patients are poorly understood. In this study, we investigated sleep pattern and circadian rhythms in Presenilin-1/2 conditional knockout (DKO) mice. Assessment of EEG and EMG recordings showed that DKO mice displayed increased NREM sleep time but not REM sleep during the dark phase compared to WT mice at the age of two months; at the age of six months, the DKO mice showed increased wakefulness periods and decreased total time spent in both NREM and REM sleep. WT exhibited time-of-day dependent modulation of contextual and cued memory. Compared with WT mice, 4-month-old DKO mice exhibited the deficiency regardless trained and tested in the same light/night phase or not. Particularly interesting was that DKO showed circadian modulation deficiency when trained in the resting period but not in the active period. Long noncoding RNAs (lncRNAs) are typically defined as transcripts longer than 200 nucleotides, and they have rhythmic expression in mammals. To date no study has investigated rhythmic lncRNA expression in Alzheimer's disease. We applied RNA-seq technology to profile hippocampus expression of lncRNAs in DKO mice during the light (/resting) and dark (/active) phases and performed gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses of the cis lncRNA targets. Expression alteration of lncRNAs associated with immune response and metallodipeptidase activity may contribute to the circadian disruptions of DKO mice. Especially we identified some LncRNAs which expression change oppositely between day and light in DKO mice compared to WT mice and are worthy to be studied further. Our results exhibited the circadian rhythm sleep disorders and a noteworthy time-of-day-dependent memory deficiency in AD model mice and provide a useful resource for studying the expression and function of lncRNAs during circadian disruptions in Alzheimer's disease.
Assuntos
Doença de Alzheimer , RNA Longo não Codificante , Transtornos do Sono do Ritmo Circadiano , Animais , Camundongos , Doença de Alzheimer/genética , Ritmo Circadiano/genética , Mamíferos/genética , Camundongos Knockout , RNA Longo não Codificante/genética , Sono/fisiologia , Transtornos do Sono do Ritmo Circadiano/genéticaRESUMO
Circadian rhythms, present in most phyla across life, are biological oscillations occurring on a daily cycle. Since the discovery of their molecular foundations in model organisms, many inputs that modify this tightly controlled system in humans have been identified. Polygenic variations and environmental factors influence each person's circadian rhythm, contributing to the trait known as chronotype, which manifests as the degree of morning or evening preference in an individual. Despite normal variation in chronotype, much of society operates on a "one size fits all" schedule that can be difficult to adjust to, especially for certain individuals whose endogenous circadian phase is extremely advanced or delayed. This is a public health concern, as phase misalignment in humans is associated with a number of adverse health outcomes. Additionally, modern technology (such as electric lights and computer, tablet, and phone screens that emit blue light) and lifestyles (such as shift or irregular work schedules) are disrupting circadian consistency in an increasing number of people. Though medical and lifestyle interventions can alleviate some of these issues, growing research on endogenous circadian variability and sensitivity suggests that broader social changes may be necessary to minimize the impact of circadian misalignment on health.
Assuntos
Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Sono/genética , Sono/fisiologia , Humanos , Síndrome do Jet Lag/etiologia , Transtornos do Sono do Ritmo Circadiano/etiologia , Transtornos do Sono do Ritmo Circadiano/genética , Transtornos do Sono do Ritmo Circadiano/fisiopatologia , Tolerância ao Trabalho Programado/fisiologiaRESUMO
The human DNA methylome is responsive to our environment, but its dynamics remain underexplored. We investigated the temporal changes to DNA methylation (DNAme) in relation to recovery from a shift work disorder (SWD) by performing a paired epigenome-wide analysis in an occupational cohort of 32 shift workers (25 men, age = 43.8 ± 8.8 years, 21 SWD cases). We found that the effect of vacation on DNAme was more prominent in the SWD-group as compared to controls, with respect to the amount of significantly differentially methylated positions (DMPs; Punadj < 0.05) 6.5 vs 3.7%, respectively. The vast majority (78%) of these DMPs were hypomethylated in SWD but not in controls (27%) during the work period. The Gene Ontology Cellular component "NMDA glutamate receptor" (PFDR < 0.05) was identified in a pathway analysis of the top 30 genes in SWD. In-depth pathway analyses revealed that the Reactome pathway "CREB phosphorylation through the activation of CaMKII" might underlie the recovery. Furthermore, three DMPs from this pathway, corresponding to GRIN2C, CREB1, and CAMK2B, correlated with the degree of recovery (Punadj < 0.05). Our findings provide evidence for the dynamic nature of DNAme in relation to the recovery process from a circadian disorder, with biological relevance of the emerging pathways.
Assuntos
Metilação de DNA , Epigênese Genética , Jornada de Trabalho em Turnos/efeitos adversos , Transtornos do Sono do Ritmo Circadiano/genética , Adulto , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Estudos de Casos e Controles , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de N-Metil-D-Aspartato/genéticaRESUMO
Endometrial cancer (EC) is one of the most common gynecologic malignancies, and the incidence rate of night shift among women workers is higher than that in the general population. Circadian rhythm disorder, mainly rhythm gene, is related to various tumor onset, including EC. This study described the sleep/night-shift features of EC patients, explored the mechanism of the circadian clock gene PER and investigated prognostic and functional values of Per1 caused by night shift. A total of 619 subjects were enrolled and divided into two groups according to night-shift duties (rhythm group and control group), analyzed for clinical risk factors and night shift features of endometrial carcinoma. Then samples were randomly selected for sequencing and western blot were performed, and the function of overexpressed PER1 in ishikawa cells was explored. We noticed that severer EC patients experienced night-shift more frequently and with longer durations. A total of 58,174 differentially expressed genes were discovered, mainly rhythm genes and related to up and downstream regulatory genes. Western blot showed that the rhythm group had elevated protein expression of BCAS4, TUBB2B and RSPO4, and decreased expression of PER1 and PER2 in night-shift. In TCGA-EC datasets, PER1 was decreased in the EC patients with a significantly positive correlation with PER2, and higher PER1 expression indicated longer survival, opposite to TUBB2B. The research of overexpressing PER1 gene in EC ishikawa cells found that PER1 can promote apoptosis, expression of TNF-a, IL-6 and PD-1/PD-L1, inhibit the tumor invasion and expression of TUBB2B gene. Together, EC severity was associated with night-shift and rhythm disorders. The rhythm relating factors PER1, TUBB2B and tumor immune factors may regulate the mechanisms of EC onset and progression.
Assuntos
Neoplasias do Endométrio , Proteínas Circadianas Period/metabolismo , Transtornos do Sono do Ritmo Circadiano , Tubulina (Proteína)/metabolismo , Adulto , Idoso , Transtornos Cronobiológicos/genética , Transtornos Cronobiológicos/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Feminino , Redes Reguladoras de Genes , Humanos , Pessoa de Meia-Idade , Proteínas Circadianas Period/genética , Transtornos do Sono do Ritmo Circadiano/genética , Transtornos do Sono do Ritmo Circadiano/metabolismo , Transcriptoma , Tubulina (Proteína)/genéticaRESUMO
Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Criptocromos/genética , Mutação , Transtornos do Sono do Ritmo Circadiano/genética , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Criptocromos/metabolismo , Feminino , Estudos de Associação Genética , Células HEK293 , Humanos , Masculino , Transtornos do Sono do Ritmo Circadiano/metabolismoRESUMO
From an evolutionary point of view, vitamin D and melatonin appeared very early and share functions related to defense mechanisms. In the current clinical setting, vitamin D is exclusively associated with phosphocalcic metabolism. Meanwhile, melatonin has chronobiological effects and influences the sleep-wake cycle. Scientific evidence, however, has identified new actions of both molecules in different physiological and pathological settings. The biosynthetic pathways of vitamin D and melatonin are inversely related relative to sun exposure. A deficiency of these molecules has been associated with the pathogenesis of cardiovascular diseases, including arterial hypertension, neurodegenerative diseases, sleep disorders, kidney diseases, cancer, psychiatric disorders, bone diseases, metabolic syndrome, and diabetes, among others. During aging, the intake and cutaneous synthesis of vitamin D, as well as the endogenous synthesis of melatonin are remarkably depleted, therefore, producing a state characterized by an increase of oxidative stress, inflammation, and mitochondrial dysfunction. Both molecules are involved in the homeostatic functioning of the mitochondria. Given the presence of specific receptors in the organelle, the antagonism of the renin-angiotensin-aldosterone system (RAAS), the decrease of reactive species of oxygen (ROS), in conjunction with modifications in autophagy and apoptosis, anti-inflammatory properties inter alia, mitochondria emerge as the final common target for melatonin and vitamin D. The primary purpose of this review is to elucidate the common molecular mechanisms by which vitamin D and melatonin might share a synergistic effect in the protection of proper mitochondrial functioning.
Assuntos
Melatonina/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/genética , Vitamina D/metabolismo , Animais , Apoptose/genética , Humanos , Melatonina/genética , Mitocôndrias/genética , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina/genética , Estações do Ano , Transtornos do Sono do Ritmo Circadiano/genética , Transtornos do Sono do Ritmo Circadiano/metabolismo , Transtornos do Sono do Ritmo Circadiano/patologia , Vitamina D/genéticaRESUMO
BACKGROUND & AIMS: Sleep disruption modifies the immune system and can trigger flares of inflammatory bowel diseases (IBD). Changes in expression of clock genes have been reported in patients with IBD. We investigated whether a change in the circadian clock is an early event in development of IBD. METHODS: We performed a prospective study of patients younger than 21 years old who underwent diagnostic endoscopies at the pediatric and adult gastroenterology units at the Tel Aviv Sourasky Medical Center from August 2016 through August 2017. Questionnaires were completed by 32 patients with IBD (8-21 years old) and 18 healthy individuals (controls) that provided data on demographics, sleep, disease activity scores. We also obtained data on endoscopic scores, anthropometric parameters, blood level of C-reactive protein (CRP), and fecal level of calprotectin. Peripheral blood and intestinal mucosa samples were analyzed for expression levels of clock gene (CLOCK, BMAL1, CRY1, CRY2, PER1, and PER2). RESULTS: Levels of CRP and fecal calprotectin were significantly higher in patients with IBD compared with controls (P<.05). Expression levels of clock genes (CLOCK, CRY1, CRY2, PER1, and PER2) were significantly lower in inflamed intestinal mucosa from patients compared with intestinal mucosa from controls (P<.05). Expression levels of all clock genes except for PER2, were also significantly lower in non-inflamed intestinal mucosal tissues from patients compared with controls (P<.05). Expression levels of clock genes (CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2) were lower in white blood cells from patients with IBD compared with controls. This reduction was greater in white blood cells from patients with ulcerative colitis than in patients with Crohn's disease. CONCLUSION: Young, newly diagnosed, untreated patients with IBD have reduced expression of clock genes in inflamed and non-inflamed intestinal mucosal samples, and also in blood cells, compared with healthy individuals. Alterations in expression of clock genes might be an early event in IBD pathogenesis. ClinicalTrials.gov Identifier: NCT03662646.
Assuntos
Relógios Circadianos/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Doenças Inflamatórias Intestinais/genética , Adolescente , Criança , Relógios Circadianos/imunologia , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/imunologia , Colonoscopia , Feminino , Expressão Gênica , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Leucócitos/imunologia , Masculino , Estudos Prospectivos , Transtornos do Sono do Ritmo Circadiano/genética , Transtornos do Sono do Ritmo Circadiano/imunologiaRESUMO
Circadian clocks are endogenous oscillators that control 24-h physiological and behavioral processes. The central circadian clock exerts control over myriad aspects of mammalian physiology, including the regulation of sleep, metabolism, and the immune system. Here, we review advances in understanding the genetic regulation of sleep through the circadian system, as well as the impact of dysregulated gene expression on metabolic function. We also review recent studies that have begun to unravel the circadian clock's role in controlling the cardiovascular and nervous systems, gut microbiota, cancer, and aging. Such circadian control of these systems relies, in part, on transcriptional regulation, with recent evidence for genome-wide regulation of the clock through circadian chromosome organization. These novel insights into the genomic regulation of human physiology provide opportunities for the discovery of improved treatment strategies and new understanding of the biological underpinnings of human disease.
Assuntos
Ritmo Circadiano/genética , Genômica , Animais , Relógios Circadianos/genética , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno/genética , Humanos , Sistema Imunitário/metabolismo , Transdução de Sinais/genética , Transtornos do Sono do Ritmo Circadiano/genética , Transtornos do Sono do Ritmo Circadiano/patologiaRESUMO
PURPOSE OF REVIEW: To integrate evidence on the role of circadian rhythm in male reproduction. Several studies report on various aspects of the association between the circadian system and male reproductive function in animals and humans both in physiological condition as well as in the case of subfertility. RECENT FINDINGS: Epidemiological data demonstrate diurnal and seasonal changes as well as the effect of sleep/wake cycles on the quality of semen. Rare and common genetic variation in circadian clock genes in humans and animal models support the role of circadian rhythms in male fertility in humans. SUMMARY: Current data support the modest effect of the circadian clock on male reproductive potential; however, the evidence available is still fragmented and inconclusive. Additional well designed and sufficiently powered studies are needed to delineate the role of the circadian clock both in cause and potential interventional and preventive approaches in male subfertility.
Assuntos
Ritmo Circadiano/fisiologia , Reprodução/fisiologia , Animais , Proteínas CLOCK/genética , Relógios Circadianos/genética , Humanos , Infertilidade Masculina/epidemiologia , Infertilidade Masculina/etiologia , Infertilidade Masculina/genética , Infertilidade Masculina/prevenção & controle , Masculino , Medicina Preventiva/métodos , Reprodução/genética , Estações do Ano , Análise do Sêmen , Transtornos do Sono do Ritmo Circadiano/complicações , Transtornos do Sono do Ritmo Circadiano/epidemiologia , Transtornos do Sono do Ritmo Circadiano/genética , Transtornos do Sono do Ritmo Circadiano/terapiaRESUMO
Delayed sleep-wake phase disorder (DSWPD) is a subtype of circadian rhythm sleep-wake disorders, and is characterized by an inability to fall asleep until late at night and wake up at a socially acceptable time in the morning. The study aim was to identify low-frequency nonsense and missense variants that are associated with DSWPD. Candidate variants in circadian rhythm-related genes were extracted by integration of genetic variation databases and in silico assessment. We narrowed down the candidates to six variants. To examine whether the six variants are associated with DSWPD, we performed an association study in 236 Japanese patients with DSWPD and 1436 controls. A low-frequency missense variant (p.Val1205Met) in PER2 showed a significant association with DSWPD (2.5% in cases and 1.1% in controls, P = 0.026, odds ratio (OR) = 2.32). The variant was also associated with idiopathic hypersomnia known to have a tendency toward phase delay (P = 0.038, OR = 2.07). PER2 forms a heterodimer with CRY, and the heterodimer plays an important role in the regulation of circadian rhythms. Val1205 is located in the CRY-binding domain of PER2 and was hypothesized to interact with CRY. The p.Val1205Met substitution could be a potential genetic marker for DSWPD.
Assuntos
Povo Asiático/genética , Variação Genética/genética , Mutação de Sentido Incorreto/genética , Proteínas Circadianas Period/genética , Transtornos do Sono do Ritmo Circadiano/genética , Alelos , Estudos de Casos e Controles , Frequência do Gene/genética , HumanosRESUMO
STUDY OBJECTIVES: We evaluated the relationship between leukocyte telomere length (LTL) and sleep duration, insomnia symptoms, and circadian rhythm, to test whether sleep and chronobiological dysregulations are associated with cellular aging. METHODS: Data from the Netherlands Study of Depression and Anxiety (N = 2,936) were used at two waves 6 years apart, to measure LTL. Telomeres shorten during the life span and are important biomarkers for cellular aging. LTL was assessed by qualitative polymerase chain reaction and converted into base pair number. Sleep parameters were: sleep duration and insomnia symptoms from the Insomnia Rating Scale. Circadian rhythm variables were: indication of Delayed Sleep Phase Syndrome (DSPS), mid-sleep corrected for sleep debt on free days (MSFsc), sleep-onset time, and self-reported chronotype, from the Munich Chronotype Questionnaire. Generalized estimating equations analyzed the associations between LTL, sleep, and chronobiological factors, adjusted for baseline age, sex, North European ancestry, and additionally for current smoking, depression severity, obesity, and childhood trauma. RESULTS: Indicators of delayed circadian rhythm showed a strong and consistent effect on LTL, after adjustment for sociodemographic and health indicators. Late MSFsc (B = -49.9, p = .004), late sleep-onset time (B = -32.4, p = .001), indication of DSPS (B = -73.8, p = .036), and moderately late chronotype in adulthood (B = -71.6, p = .003) were associated with significantly shorter LTL across both waves; whereas sleep duration and insomnia symptoms were not. Extremely early chronotype showed significantly less LTL shortening than intermediate chronotype (B = 161.40, p = .037). No predictors showed accelerated LTL attrition over 6 years. CONCLUSIONS: Individuals with delayed circadian rhythm have significantly shorter LTL, but not faster LTL attrition rates.
Assuntos
Envelhecimento/fisiologia , Senescência Celular/fisiologia , Transtornos do Sono do Ritmo Circadiano/fisiopatologia , Sono/fisiologia , Encurtamento do Telômero/fisiologia , Adulto , Ansiedade/epidemiologia , Ansiedade/genética , Ansiedade/fisiopatologia , Ritmo Circadiano/fisiologia , Estudos de Coortes , Depressão/epidemiologia , Depressão/genética , Depressão/fisiopatologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Transtornos do Sono do Ritmo Circadiano/epidemiologia , Transtornos do Sono do Ritmo Circadiano/genética , Inquéritos e QuestionáriosRESUMO
Clock genes that comprise the circadian clock system control various physiological functions. Delayed sleep-wake phase disorder (DSWPD) and night eating syndrome (NES) are characterized by delayed sleep and meal timing, respectively. We estimated that clock gene expression rhythms in DSWPD patients may be delayed in comparison with the healthy subjects due to delayed melatonin secretion rhythms, producing eveningness chronotype in these individuals. However, it was difficult to estimate which clock gene expression rhythms were delayed or not in NES patients, because previous studies revealed that melatonin secretion rhythm was a little delayed compared with healthy individuals and that chronotype of NES patients depended on the individuals. Therefore, we examined expression rhythms of clock genes such as Period3 (Per3), nuclear receptor subfamily 1, group D, member 1 (Nr1d1) and Nr1d2 in these patients. Further, we expected sleep and meal patterns in DSWPD and NES patients may be more diverse than patterns observed in healthy subjects, and thus analyzed relationships among clock gene expression rhythms, sleep quality, sleep midpoint time, and meal times. We enrolled healthy male participants along with DSWPD and NES male patients, and asked all participants to answer questionnaires and to keep diaries to record information on their sleep and meals. Further, we asked them to collect 5-10 beard follicle samples, 6 times every 4 h. We measured clock gene expression rhythms using total RNA extracted from beard follicle cells. Peak time of clock gene expression in the NES group showed more diversity than the other groups, and that in the DSWPD group was delayed compared with the control group. In addition, the peak time of clock gene expression was negatively correlated with sleep quality and positively correlated with meal time after a long fast. Amplitudes of clock gene expression, especially Per3, positively responded to better mental and physical conditions as well as with better sleep quality. Results of this study suggest that peak times of clock gene expression in NES patients depended on the individuals; some patients with NES showed similar clock gene expression rhythm to healthy subjects, and other patients with NES showed similar to DSWPD patients. Moreover, this study suggests that meal time after a long fast may influence more determination in clock gene expression rhythms than the time of breakfast. Therefore, this study also indicates that Per3 clock gene may be one of the parameters that will help us understand sleep and meal rhythm disturbances.
Assuntos
Ritmo Circadiano/fisiologia , Expressão Gênica/fisiologia , Refeições/fisiologia , Síndrome do Comer Noturno/genética , Transtornos do Sono do Ritmo Circadiano/genética , Adulto , Comportamento Alimentar/fisiologia , Humanos , Masculino , Melatonina/metabolismo , Sono/genéticaRESUMO
Melatonin secretion and polysomnography (PSG) were compared among a group of healthy adolescents who were at high familial risk for bipolar disorder (HR) and a second group at low familial risk (LR). Adolescent participants (nâ¯=â¯12) were a mean age 14 ± 2.3 years and included 8 females and 4 males. Saliva samples were collected under standardized condition light (red light) and following a 200 lux light exposure over two consecutive nights in a sleep laboratory. Red Light Melatonin onset (RLMO) was defined as saliva melatonin level exceeding the mean of the first 3 readings plus 2 standard deviations. Polysomnography was also completed during each night. HR youth, relative to LR, experienced a significantly earlier melatonin onset following 200 lux light exposure. Polysomnography revealed that LR youth, relative to HR, spent significantly more time in combined stages 3 and 4 (deep sleep) following red light exposure. Additionally, regardless of the group status (HR or LR), there was no significant difference in Red Light Melatonin Onset recorded at home or in the laboratory, implying its feasibility and reliability.
Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/metabolismo , Predisposição Genética para Doença , Melatonina/metabolismo , Estimulação Luminosa/métodos , Saliva/metabolismo , Adolescente , Adulto , Biomarcadores/química , Biomarcadores/metabolismo , Transtorno Bipolar/genética , Criança , Ritmo Circadiano/fisiologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Polissonografia/tendências , Reprodutibilidade dos Testes , Saliva/química , Sono/fisiologia , Transtornos do Sono do Ritmo Circadiano/diagnóstico , Transtornos do Sono do Ritmo Circadiano/genética , Transtornos do Sono do Ritmo Circadiano/metabolismoRESUMO
Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia. We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 ± 7.3), and in relation to shift work disorder in an occupational cohort (26 men, aged 44.9 ± 9.0). The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: "Nervous System Development" (FDR P value < 0.05). We found that 78% of the DMPs were hypomethylated in cases in both cohorts, suggesting that insufficient sleep may be associated with loss of DNA methylation. A karyoplot revealed clusters of DMPs at various chromosomal regions, including 12 DMPs on chromosome 17, previously associated with Smith-Magenis syndrome, a rare condition comprising disturbed sleep and inverse circadian rhythm. Our findings give novel insights into the DNA methylation patterns associated with sleep loss, possibly modifying processes related to neuroplasticity and neurodegeneration. Future prospective studies are needed to confirm the observed associations.
Assuntos
Metilação de DNA/genética , Distúrbios do Início e da Manutenção do Sono/genética , Sono/genética , Adulto , Ritmo Circadiano/genética , Estudos Transversais , Epigênese Genética/genética , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transtornos do Sono do Ritmo Circadiano/genéticaRESUMO
BACKGROUND: Circadian clocks are found in nearly all organisms, from bacteria to mammals, and ensure that behavioral and physiological processes occur at optimal times of day and in the correct temporal order. It is becoming increasingly clear that chronic circadian misalignment (CCM), such as occurs in shift workers or as a result of aberrant sleeping and eating schedules common to modern society, has profound metabolic and cognitive consequences, but the proximate mechanisms connecting CCM with reduced organismal health are unknown. Furthermore, it has been difficult to disentangle whether the health effects are directly induced by misalignment or are secondary to the alterations in sleep and activity levels that commonly occur with CCM. Here, we investigated the consequences of CCM in the powerful model system of the fruit fly, Drosophila melanogaster. We subjected flies to daily 4-h phase delays in the light-dark schedule and used the Drosophila Activity Monitoring (DAM) system to continuously track locomotor activity and sleep while simultaneously monitoring fly lifespan. RESULTS: Consistent with previous results, we find that exposing flies to CCM leads to a ~ 15% reduction in median lifespan in both male and female flies. Importantly, we demonstrate that the reduced longevity occurs independent of changes in overall sleep or activity. To uncover potential molecular mechanisms of CCM-induced reduction in lifespan, we conducted whole body RNA-sequencing to assess differences in gene transcription between control and misaligned flies. CCM caused progressive, large-scale changes in gene expression characterized by upregulation of genes involved in response to toxic substances, aging and oxidative stress, and downregulation of genes involved in regulation of development and differentiation, gene expression and biosynthesis. CONCLUSIONS: Many of these gene expression changes mimic those that occur during natural aging, consistent with the idea that CCM results in premature organismal decline, however, we found that genes involved in lipid metabolism are overrepresented among those that are differentially regulated by CCM and aging. This category of genes is also among the earliest to exhibit CCM-induced changes in expression, thus highlighting altered lipid metabolism as a potentially important mediator of the negative health consequences of CCM.
Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/genética , Longevidade/genética , Transtornos do Sono do Ritmo Circadiano/genética , Animais , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Locomoção/genética , Longevidade/fisiologia , Masculino , Estresse Oxidativo , Jornada de Trabalho em Turnos , Transtornos do Sono do Ritmo Circadiano/fisiopatologiaRESUMO
Mutations in fused in sarcoma (Fus) cause familial amyotrophic lateral sclerosis (ALS) and occasionally frontotemporal dementia. Here we report the establishment and characterization of a novel knockin (KI) rat model expressing a Fus point mutation (R521C) via CRISPR/Cas9. The mutant animals developed adult-onset learning and memory behavioral deficits, with reduced spine density in hippocampal neurons. Remarkably, sleep-wake cycle and circadian abnormalities preceded the onset of cognitive deficit. RNA-seq study further demonstrated altered expression of some key sleep and circadian regulators, such as orexin/hypocretin receptor type 2 and casein kinase 1 epsilon, in the mutant rats. Therefore, we have established a rodent model expressing physiological level of a pathogenic mutant FUS, and we found cognitive impairment as a main behavioral deficit at mid age. Furthermore, we have revealed a new role of FUS in sleep and circadian regulation and demonstrated that functional change in FUS could cause sleep-wake and circadian disturbance as early symptoms.
Assuntos
Comportamento Animal , Transtornos Cronobiológicos/genética , Disfunção Cognitiva/genética , Proteína FUS de Ligação a RNA/metabolismo , Sono/genética , Vigília/genética , Fatores Etários , Animais , Células Cultivadas , Modelos Animais de Doenças , Eletroencefalografia , Eletromiografia , Embrião de Mamíferos , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Transtornos do Sono do Ritmo Circadiano/genéticaRESUMO
Parkinson's disease patients report disturbed sleep patterns long before motor dysfunction. Here, in parkin and pink1 models, we identify circadian rhythm and sleep pattern defects and map these to specific neuropeptidergic neurons in fly models and in hypothalamic neurons differentiated from patient induced pluripotent stem cells (iPSCs). Parkin and Pink1 control the clearance of mitochondria by protein ubiquitination. Although we do not observe major defects in mitochondria of mutant neuropeptidergic neurons, we do find an excess of endoplasmic reticulum-mitochondrial contacts. These excessive contact sites cause abnormal lipid trafficking that depletes phosphatidylserine from the endoplasmic reticulum (ER) and disrupts the production of neuropeptide-containing vesicles. Feeding mutant animals phosphatidylserine rescues neuropeptidergic vesicle production and acutely restores normal sleep patterns in mutant animals. Hence, sleep patterns and circadian disturbances in Parkinson's disease models are explained by excessive ER-mitochondrial contacts, and blocking their formation or increasing phosphatidylserine levels rescues the defects in vivo.