Splice variants of DOMINO control Drosophila circadian behavior and pacemaker neuron maintenance.

Circadian clocks control daily rhythms in behavior and physiology. In Drosophila, the small ventral lateral neurons (sLNvs) expressing PIGMENT DISPERSING FACTOR (PDF) are the master pacemaker neurons generating locomotor rhythms. Despite the importance of sLNvs and PDF in circadian behavior, little is known about factors that control sLNvs maintenance and PDF accumulation. Here, we identify the Drosophila SWI2/SNF2 protein DOMINO (DOM) as a key regulator of circadian behavior. Depletion of DOM in circadian neurons eliminates morning anticipatory activity under light dark cycle and impairs behavioral rhythmicity in constant darkness. Interestingly, the two major splice variants of DOM, DOM-A and DOM-B have distinct circadian functions. DOM-A depletion mainly leads to arrhythmic behavior, while DOM-B knockdown lengthens circadian period without affecting the circadian rhythmicity. Both DOM-A and DOM-B bind to the promoter regions of key pacemaker genes period and timeless, and regulate their protein expression. However, we identify that only DOM-A is required for the maintenance of sLNvs and transcription of pdf. Lastly, constitutive activation of PDF-receptor signaling rescued the arrhythmia and period lengthening of DOM downregulation. Taken together, our findings reveal that two splice variants of DOM play distinct roles in circadian rhythms through regulating abundance of pacemaker proteins and sLNvs maintenance

Understanding the role of chromatin remodeling in the regulation of circadian transcription in Drosophila.

Circadian clocks enable organisms to anticipate daily changes in the environment and coordinate temporal rhythms in physiology and behavior with the 24-h day-night cycle. The robust cycling of circadian gene expression is critical for proper timekeeping, and is regulated by transcription factor binding, RNA polymerase II (RNAPII) recruitment and elongation, and post-transcriptional mechanisms. Recently, it has become clear that dynamic alterations in chromatin landscape at the level of histone posttranslational modification and nucleosome density facilitate rhythms in transcription factor recruitment and RNAPII activity, and are essential for progression through activating and repressive phases of circadian transcription. Here, we discuss the characterization of the BRAHMA (BRM) chromatin-remodeling protein in Drosophila in the context of circadian clock regulation. By dissecting its catalytic vs. non-catalytic activities, we propose a model in which the non-catalytic activity of BRM functions to recruit repressive factors to limit the transcriptional output of CLOCK (CLK) during the active phase of circadian transcription, while the primary function of the ATP-dependent catalytic activity is to tune and prevent over-recruitment of negative regulators by increasing nucleosome density. Finally, we divulge ongoing efforts and investigative directions toward a deeper mechanistic understanding of transcriptional regulation of circadian gene expression at the chromatin level

Thoughtful Days and Valenced Nights: How Much Will You Think About the Problem?

Research investigating risk preference has pointed towards motivation and ability as important factors for determining the strength and likelihood of the framing effect. In the current study we explored the influence of individual differences in motivation and ability through circadian rhythm. We predicted that during circadian off-times participants would exhibit stronger framing effects whereas framing effects would be relatively weaker during on-times. Six-hundred and eighty five individuals took part in the study; the findings supported our hypothesis, revealing a diurnal pattern of risk responding that varies across the 24-hour circadian cycle. Key Words:

The Associations Between Circadian Genetic Factors And Cancer Survival

The circadian rhythm controls a range of important biological behaviors with a 24-hour cycle. The mammalian biological clock is a layered network of vibrators with a master clock locating in the neurons of suprachiasmatic nucleus (SCN) in the hypothalamus and a set of core and related circadian genes. Several lines of evidence from previous studies suggested the relationships between tumorigenesis and circadian rhythm disruption. However, the effects of circadian genetic factors in cancer survival remains uncertain. Therefore, it is important to review and explore the circadian genetic factors which might be linked to cancer survival. This paper aimed to evaluate the potential associations between circadian genetic factors and cancer survival by summarizing 30 epidemiological studies and searching 2 databases. The circadian genetic factors identified included both gene expression and SNPs. Our results showed that 16 circadian genes, PER1, PER2, PER3, CRY1, CRY2, BMAL1, CLOCK, NPAS2, NPAS3, TIMELESS, RORA, RORC, NR1D2, CK1ε, DEC1 and TIPIN, were significantly related to cancer survival across several types of cancer. The associations between circadian genes and cancer survival differed among different genes and cancer types

Systems analysis of circadian time-dependent neuronal epidermal growth factor receptor signaling

BACKGROUND: Identifying the gene regulatory networks governing physiological signal integration remains an important challenge in circadian biology. Epidermal growth factor receptor (EGFR) has been implicated in circadian function and is expressed in the suprachiasmatic nuclei (SCN), the core circadian pacemaker. The transcription networks downstream of EGFR in the SCN are unknown but, by analogy to other SCN inputs, we expect the response to EGFR activation to depend on circadian timing. RESULTS: We have undertaken a systems-level analysis of EGFR circadian time-dependent signaling in the SCN. We collected gene-expression profiles to study how the SCN response to EGFR activation depends on circadian timing. Mixed-model analysis of variance (ANOVA) was employed to identify genes with circadian time-dependent EGFR regulation. The expression data were integrated with transcription-factor binding predictions through gene group enrichment analyses to generate robust hypotheses about transcription-factors responsible for the circadian phase-dependent EGFR responses. CONCLUSION: The analysis results suggest that the transcriptional response to EGFR signaling in the SCN may be partly mediated by established transcription-factors regulated via EGFR transription-factors (AP1, Ets1, C/EBP), transcription-factors involved in circadian clock entrainment (CREB), and by core clock transcription-factors (Rorα). Quantitative real-time PCR measurements of several transcription-factor expression levels support a model in which circadian time-dependent EGFR responses are partly achieved by circadian regulation of upstream signaling components. Our study suggests an important role for EGFR signaling in SCN function and provides an example for gaining physiological insights through systems-level analysis

Nerve growth factor, brain-derived neurotrophic factor, and the chronobiology of mood: a new insight into the "neurotrophic hypothesis"

The light information pathways and their relationship with the body rhythms have generated a new insight into the neurobiology and the neurobehavioral sciences, as well as into the clinical approaches to human diseases associated with disruption of circadian cycles. Light-based strategies and/or drugs acting on the circadian rhythms have widely been used in psychiatric patients characterized by mood-related disorders, but the timing and dosage use of the various treatments, although based on international guidelines, are mainly dependent on the psychiatric experiences. Further, many efforts have been made to identify biomarkers able to disclose the circadian-related aspect of diseases, and therefore serve as diagnostic, prognostic, and therapeutic tools in clinic to assess the different mood-related symptoms, including pain, fatigue, sleep disturbance, loss of interest or pleasure, appetite, psychomotor changes, and cognitive impairments. Among the endogenous factors suggested to be involved in mood regulation, the neurotrophins, nerve growth factor, and brain-derived neurotrophic factor show anatomical and functional link with the circadian system and mediate some of light-induced effects in brain. In addition, in humans, both nerve growth factor and brain-derived neurotrophic factor have showed a daily rhythm, which correlate with the morningness–eveningness dimensions, and are influenced by light, suggesting their potential role as biomarkers for chronotypes and/or chronotherapy. The evidences of the relationship between the diverse mood-related disorders, with a specific focus on depression, and neurotrophins are reviewed and discussed herein in terms of their circadian significance, and potential translation into clinical practice

Circadian regulation of human immunodeficiency virus type 1 replication

Human immunodeficiency virus (HIV) causes significant health problems globally, and despite improvements in therapy there remains no cure. Viral replication is reliant on the host and many physiological processes are influenced by endogenous 24 h oscillations, called circadian rhythms. On a cellular level, circadian transcription factors generate daily oscillations in gene expression. As there is an emerging role for clock components in regulating viral replication, we studied the interplay between the circadian clock and HIV-1. Using a cellular circadian model system, we demonstrate rhythmic HIV-1 replication, which has a period of ~24 hours and is regulated by the cell-intrinsic clock. Pharmacological modulation of circadian transcription factors altered HIV-1 replication across multiple HIV-1 subtypes, indicating pan-genotypic anti-viral potential. Genetic disruption of the circadian activator BMAL1 reduced HIV-1 replication and blunted rhythmicity in transcription. In contrast, knockdown of the circadian repressor REV-ERB enhanced viral replication. We show binding of clock factors to the viral genome and reveal time differential binding of circadian nuclear receptors REV-ERB and ROR, which compete for binding to a ROR response element in the HIV-1 promoter. We demonstrate circadian regulation of HIV-1 host factors, which will influence rhythmic HIV replication. Moreover, we uncover a role for the circadian machinery in regulating latent HIV-1 infection. Bromodomain proteins and salt inducible kinases are both involved in circadian networks, and our findings indicate that they regulate reactivation from latency. Our work provides novel insights in the circadian regulation of HIV-1 replication by molecular components of the clock. Circadian modifiers with anti-viral properties could uncover novel drug targets, which may augment existing treatments and will help to inform HIV therapy and management

Ethnic differences and heritability of blood pressure circadian rhythm in African and European American youth and young adults

Background: The aim of this study was to investigate whether blood pressure (BP) circadian rhythm in African Americans differed from that in European Americans. We further examined the genetic and/or environmental sources of variances of the BP circadian rhythm parameters and the extent to which they depend on ethnicity or sex. Method: Quantification of BP circadian rhythm was obtained using Fourier transformation from the ambulatory BP monitoring data of 760 individuals (mean age, 17.2 +/- 3.3; 322 twin pairs and 116 singletons; 351 African Americans). Results: BP circadian rhythm showed a clear difference by ethnic group with African Americans having a lower amplitude (P = 1.5e-08), a lower percentage rhythm (P = 2.8e-11), a higher MESOR (P = 2.5e-05) and being more likely not to display circadian rhythm (P = 0.002) or not in phase (P = 0.003). Familial aggregation was identified for amplitude, percentage rhythm and acrophase with genetic factors and common environmental factors together accounting for 23 to 33% of the total variance of these BP circadian rhythm parameters. Unique environmental factors were the largest contributor explaining up to 67--77% of the total variance of these parameters. No sex or ethnicity difference in the variance components of BP circadian rhythm was observed. Conclusion: This study suggests that ethnic differences in BP circadian rhythm already exist in youth with African Americans having a dampened circadian rhythm and better BP circadian rhythm may be achieved by changes in environmental factors

p75 neurotrophin receptor is a clock gene that regulates oscillatory components of circadian and metabolic networks.

The p75 neurotrophin receptor (p75(NTR)) is a member of the tumor necrosis factor receptor superfamily with a widespread pattern of expression in tissues such as the brain, liver, lung, and muscle. The mechanisms that regulate p75(NTR) transcription in the nervous system and its expression in other tissues remain largely unknown. Here we show that p75(NTR) is an oscillating gene regulated by the helix-loop-helix transcription factors CLOCK and BMAL1. The p75(NTR) promoter contains evolutionarily conserved noncanonical E-box enhancers. Deletion mutagenesis of the p75(NTR)-luciferase reporter identified the -1039 conserved E-box necessary for the regulation of p75(NTR) by CLOCK and BMAL1. Accordingly, gel-shift assays confirmed the binding of CLOCK and BMAL1 to the p75(NTR-)1039 E-box. Studies in mice revealed that p75(NTR) transcription oscillates during dark and light cycles not only in the suprachiasmatic nucleus (SCN), but also in peripheral tissues including the liver. Oscillation of p75(NTR) is disrupted in Clock-deficient and mutant mice, is E-box dependent, and is in phase with clock genes, such as Per1 and Per2. Intriguingly, p75(NTR) is required for circadian clock oscillation, since loss of p75(NTR) alters the circadian oscillation of clock genes in the SCN, liver, and fibroblasts. Consistent with this, Per2::Luc/p75(NTR-/-) liver explants showed reduced circadian oscillation amplitude compared with those of Per2::Luc/p75(NTR+/+). Moreover, deletion of p75(NTR) also alters the circadian oscillation of glucose and lipid homeostasis genes. Overall, our findings reveal that the transcriptional activation of p75(NTR) is under circadian regulation in the nervous system and peripheral tissues, and plays an important role in the maintenance of clock and metabolic gene oscillation

Prokineticin 2 Is a Target Gene of Proneural Basic Helix-Loop-Helix Factors for Olfactory Bulb Neurogenesis

Prokineticin 2, a cysteine-rich secreted protein, regulates diverse biological functions including the neurogenesis of olfactory bulb. Here we show that the PK2 gene is a functional target gene of proneural basic helix-loop-helix (bHLH) factors. Neurogenin 1 and MASH1 activate PK2 transcription by binding to E-box motifs on the PK2 promoter with the same set of E-boxes critical for another pair of bHLH factors, CLOCK and BMAL1, in the regulation of circadian clock. Our results establish PK2 as a common functional target gene for different bHLH transcriptional factors in mediating their respective functions