Neurospora Circadian Clock 3-variable model - sinusoidal light oscillations - PLM_52, version 1, SUBMITTED
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SUBMITTER: BioData SynthSys
PROVIDER: 487 | FAIRDOMHub | 2019-01-10
REPOSITORIES: FAIRDOMHub
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Project description:Circadian rhythms are a series of endogenous autonomous 24-hour oscillations generated by the circadian clock. At the molecular level, the circadian clock is generated by a transcription-translation feedback loop, where BMAL1 and CLOCK transcription factors of the positive arm activate the expression of CRYPTOCHROME and PERIOD (PER) genes of the negative arm as well as the circadian clock-regulated genes. In this project, we aimed at finding the interactome of PER2 protein in human U2OS osteosarcoma cell line using proximity-dependent biotin identification (BioID) technique. U2OS clones overexpressing PER2-BioID2 or BioID2 were treated with dexamethasone in order to reset the circadian rhythm, and cells were then incubated in biotin-containing media for 12 hours to label the proteins in close proximity of PER2-BioID2. Samples were collected after 36 and 48 hours of the resetting to identify the labeled proteins by mass spectrometry. In addition to known interactors such as CRY1 and CRY2, many novel interactors were identified. In summary, we obtained a network of PER2 interactome and confirmed some of the novel interactions using classical the co-immunoprecipitation method.
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Project description:The circadian system plays an essential role in regulating timing of body metabolism in humans. Indeed, circadian misalignments are strongly associated with high rates of metabolic disorders. Molecular makeup of the circadian oscillator can be deciphered in cells cultured in vitro, and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo.
We aimed at assessing molecular clock properties in dermal fibroblasts established from the skin biopsies of seventeen Type 2 diabetic obese and non-obese patients and eleven healthy controls. Following in vitro synchronization, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters.
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Project description:Circadian rhythms are cell-autonomous biological oscillations with a period of about 24 hours. Current models propose that transcriptional feedback loops are the primary mechanism for the generation of circadian oscillations1. In these models, Drosophila S2 cells are generally regarded as ‘non-rhythmic’ cells, as they do not express several canonical circadian components2,3. Using an unbiased multi-omics approach, we made the surprising discovery that Drosophila S2 cells do in fact display widespread daily rhythms. Transcriptomics and proteomics analyses revealed that hundreds of genes and their products, and in particular metabolic enzymes, are rhythmically expressed in a 24-hour cycle. Metabolomics analyses extended these findings and demonstrated that central carbon metabolism and amino acid metabolism are the principal pathways regulated in a rhythmic fashion. We thus demonstrate that 24-hour metabolic oscillations, coupled to gene expression cycles, take place in eukaryotic cells without the contribution of any known circadian regulators.
2018-07-31 | GSE102495 | GEO
Project description:Circadian rhythms are cell-autonomous biological oscillations with a period of about 24 hours. Current models propose that transcriptional feedback loops are the principal mechanism for the generation of circadian oscillations. In these models, Drosophila S2 cells are generally regarded as ‘non-rhythmic’ cells, as they do not express several canonical circadian components. Using an unbiased multi-omics approach, we made the surprising discovery that Drosophila S2 cells do in fact display widespread daily rhythms. Transcriptomics and proteomics analyses revealed that hundreds of genes and their products are rhythmically expressed in a 24-hour cycle. Metabolomics analyses extended these findings and illustrated that central carbon metabolism and amino acid metabolism are the main pathways regulated in a rhythmic fashion. We thus demonstrate that daily genome-wide oscillations, coupled to metabolic cycles, take place in eukaryotic cells without the contribution of known circadian regulators.
2018-07-31 | PXD007669 | Pride
Project description:Circadian clocks exist in almost all levels of living organisms and play elementary roles in the persistence of regular physiological and behavioural processes. Canonical transcription/translation feedback loop models portray BMAL1 (ARNTL) as one of the principal drivers of circadian periodicity in mammalian systems. In this integrated multi-omics study, we demonstrate, for the first time, 24 hr circadian oscillations in the expression levels of several transcripts and proteins in dexamethasone-synchronized Bmal1-/- mouse fibroblast cells and liver tissue slices. Intriguingly, daily oscillations were also observed in phosphoproteome profiles in the absence of this core clock gene. Our findings reveal that Bmal1 knockout radically alters the expression and phosphorylation patterns of mice hepatic proteome, which possibly attributes to considerably different sets of rhythmic candidates compared to wild-type. It is, therefore, reasonable to accentuate that circadian rhythms are not obliterated in mammalian systems due to deletion of the core clock genes.
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Project description:The circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. The clockwork orchestrates a multitude of metabolic processes as illustrated by previous global transcriptomics and proteomics studies, and the existence of daily rhythms of reduction and oxidation (redox) in a range of diverse species. However, the reciprocal question of whether metabolism can alter the clockwork remains largely unaddressed. Here we identify the pentose phosphate pathway (PPP), a critical source of cellular reducing power in the form of NADPH, as an important modulator of circadian oscillations. We show that genetic and pharmacologic inhibition of the PPP perturbs circadian gene expression and metabolic rhythms in human cells. Pharmacologic inhibition of the PPP caused similar effects in mouse tissues, and altered the pattern of rhythmic behavior in Drosophila. These manipulations also altered genome wide DNA-binding activity of the circadian transcription factors BMAL1 and CLOCK through a mechanism likely involving the redox-sensitive histone acetyltransferase p300. Thus, disruption of the PPP regulates circadian rhythms via modulation of NADPH metabolism, highlighting redox reactions as a novel connector of metabolic cycles and transcriptional oscillations in nucleated cells.
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Project description:Peripheral nervous system injuries lead to long-term neurological disability due to limited axonal regenerative ability. Injury-dependent and more recently injury-independent physiological mechanisms have provided important molecular insight into regenerative mechanisms. However, whether common molecular denominators underpinning both injury-dependent and independent biological processes exist remains unclear. We initially performed a comparative analysis of recently generated transcriptomic datasets associated with the regenerative ability of sciatic dorsal root ganglia (DRG). Surprisingly, circadian rhythms were identified as a the most significantly enriched biological process associated with regenerative capability. We demonstrate that DRG neurons possess an endogenous circadian clock with a 24h oscillations of circadian genes and that their regenerative ability displays a diurnal oscillation in a mouse model of sciatic nerve injury. Consistently, transcriptomic analysis of DRG neurons showed a significant time-of-day dependent enrichment for processes associated with neuronal development and axonal growth, for regeneration and circadian associated genes, including the core clock genes Bmal1 and Clock. Indeed, DRG-specific ablation of the non-redundant clock gene Bmal1showed that it is required for regenerative gene expression, neuronal intrinsic circadian axonal regeneration and target reinnervation. Lastly, Lithium, a chrono-active compound, enhanced nerve regeneration, in wildtype but not in clock genes Bmal1 and Cry1/2-deficient mice. Together, these data demonstrate that daily rhythms and the circadian clock fine-tune the regenerative response of DRG neurons, and they advocate for the use of chrono-active strategies in time-day dependent modulation of nerve repair.
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Project description:The circadian clock is comprised of proteins that form negative feedback loops, which regulate the timing of global gene expression in a coordinated 24 hour cycle. As a result, the plant circadian clock is responsible for regulating numerous physiological processes central to growth and survival. To date, most plant circadian clock studies have relied on diurnal transcriptome changes to elucidate molecular connections between the circadian clock and observable phenotypes in wild-type plants. Here, we have combined high-throughput RNA-sequencing and mass spectrometry to comparatively characterize the lhycca1, prr7prr9, gi and toc1 circadian clock mutant rosette transcriptome and proteome at the end-of-day and end-of-night.
2018-01-02 | PXD004763 | Pride
Project description:The mammalian circadian clock is a molecular oscillator composed of a feedback loop that involves transcriptional activators CLOCK and BMAL1, and repressors Cryptochrome (CRY) and Period (PER). Here we show that a direct CLOCK-BMAL1 target gene, Gm129, is a novel regulator of the feedback loop. ChIP analysis revealed that the CLOCK:BMAL1:CRY1 complex strongly occupies the promoter region of Gm129. Both mRNA and protein levels of GM129 exhibit high amplitude circadian oscillations in mouse liver, and Gm129 gene encodes a nuclear-localized protein that directly interacts with BMAL1 and represses CLOCK:BMAL1 activity. In vitro and in vivo protein-DNA interaction results demonstrate that, like CRY1, GM129 functions as a repressor by binding to the CLOCK:BMAL1 complex on DNA. Although Gm129-/- or Cry1-/- Gm129-/- mice retain a robust circadian rhythm, the peaks of Nr1d1 and Dbp mRNAs in liver exhibit significant phase delay compared to control. Our results suggest that, in addition to CRYs and PERs, GM129 protein contributes to the transcriptional feedback loop by modulating CLOCK:BMAL1 activity as a transcriptional repressor. Examination of 3 transcriptional regulators in mouse liver
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