Intercellular coupling between peripheral circadian oscillators by TGF-beta signaling [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA665704 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12712500.fastq.gz | Fastqsanger.gz | |||
| SRR12712501.fastq.gz | Fastqsanger.gz | |||
| SRR12712502.fastq.gz | Fastqsanger.gz | |||
| SRR12712503.fastq.gz | Fastqsanger.gz | |||
| SRR12712504.fastq.gz | Fastqsanger.gz |
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Project description:Intercellular coupling is crucial to prevent desynchronization of cell-autonomous oscillator networks and thus, the disruption of circadian tissue functions. While, neuronal oscillators within the mammalian central clock, the suprachiasmatic nucleus (SCN), couple intercellularly via the exchange of secreted neurotransmitters, intercellular coupling among peripheral oscillators is highly debated and molecular mechanisms are unknown. In our study, we show that peripheral circadian oscillators couple intercellularly via the exchange of secreted signaling molecules and identify TGF-beta as peripheral coupling factor. TGF-beta signaling induces the cAMP response element dependent, immediate-early expression of the clock gene PER2, thereby phase-adjusting the molecular circadian oscillator. Genetic or pharmacologic disruption of TGF-beta signaling causes desynchronization of cellular oscillators resulting in amplitude reduction and increased sensitivity towards Zeitgeber cues. Our findings reveal a previously unknown mechanism of peripheral coupling and open a new perspective on the importance of peripheral clock synchrony for rhythmic organ functions and circadian health.
2021-07-23 | GSE158577 | GEO
Project description:In mammalian tissues circadian gene expression can be driven by local oscillators or systemic signals controlled by the master pacemaker in the suprachiasmatic nucleus. Here we show that simulated body temperature cycles, but not peripheral oscillators, can control the rhythmic expression of Cold-Inducible RNA binding Protein (CIRP) in cultured fibroblasts. In turn, loss-of-function experiments indicate that CIRP is required for high amplitude circadian gene expression. The transcriptome-wide identification of CIRP-bound RNAs by a biotin-streptavidin based CLIP-seq procedure revealed several CIRP-bound transcripts encoding circadian oscillator proteins. One of these, CLOCK, accumulated to particularly low levels in CIRP-depleted fibroblasts. Since ectopic expression of CLOCK improved circadian gene expression in these cells, we surmise that CIRP confers robustness to circadian oscillators via the regulation of CLOCK expression.
2012-08-24 | GSE37685 | GEO
Project description:In mammalian tissues circadian gene expression can be driven by local oscillators or systemic signals controlled by the master pacemaker in the suprachiasmatic nucleus. Here we show that simulated body temperature cycles, but not peripheral oscillators, can control the rhythmic expression of Cold-Inducible RNA binding Protein (CIRP) in cultured fibroblasts. In turn, loss-of-function experiments indicate that CIRP is required for high amplitude circadian gene expression. The transcriptome-wide identification of CIRP-bound RNAs by a biotin-streptavidin based CLIP-seq procedure revealed several CIRP-bound transcripts encoding circadian oscillator proteins. One of these, CLOCK, accumulated to particularly low levels in CIRP-depleted fibroblasts. Since ectopic expression of CLOCK improved circadian gene expression in these cells, we surmise that CIRP confers robustness to circadian oscillators via the regulation of CLOCK expression. Identification of CIRP-interacting RNA molecules in NIH3T3 cells and RNA expression in NIH3T3 cells treated with Control or CIRP siRNA after incubation of the cells at 33M-BM-0C for 8 hours
2012-08-24 | E-GEOD-37685 | biostudies-arrayexpress
Project description:To screen for specific circadian outputs that may distinguish the pacemaker in the mammalian suprachiasmatic nucleus (SCN) from peripheral-type oscillators in which the canonical clockworks are similarly regulated in a circadian manner, the rhythmic behavior of the transcriptome in forskolin-stimulated NIH/3T3 fibroblasts was analyzed and compared to that found in the rat SCN in vivo and SCN2.2 cells in vitro. Similar to the scope of circadian gene expression in SCN2.2 cells and the rat SCN, NIH/3T3 fibroblasts exhibited circadian fluctuations in the expression of the core clock genes, Per2, Bmal1 (Mop3), and Cry1 and 323 functionally diverse transcripts (2.6%), many of which were involved in cell communication. Overlap in rhythmically-expressed transcripts among NIH/3T3 fibroblasts, SCN2.2 cells and the rat SCN was limited to these clock genes and four other genes that mediate fatty acid and lipid metabolism or function as nuclear factors. Compared to NIH/3T3 cells, circadian gene expression in SCN oscillators was more prevalent among cellular pathways mediating glucose metabolism and neurotransmission. Coupled with evidence for the rhythmic regulation of the inducible isoform of nitric oxide synthase, the enzyme responsible for the production of nitric oxide, in SCN2.2 cells and the rat SCN but not in fibroblasts, studies examining the effects of a NOS inhibitor on metabolic rhythms in co-cultures containing SCN2.2 cells and untreated NIH/3T3 cells suggest that this gaseous neurotransmitter may play a key role in SCN pacemaker function. Thus, this comparative analysis of circadian gene expression in SCN and non-SCN cells may have important implications in the selective identification of circadian signals involved in the coupling of SCN oscillators and the regulation of rhythmicity in downstream cells or tissues. Experiment Overall Design: Circadian profiling of the NIH/3T3 fibroblast transcriptome entailed the treatment of NIH/3T3 cells with a 15uM forskolin pulse, subsequent washout of the drug, and collection of total RNA immediately after washout and every 6 hours across two circadian cycles for each of three experiments. Timepoint values reflect the average of three samples from these biological replicates.
2008-06-14 | E-GEOD-5810 | biostudies-arrayexpress
Project description:To screen for specific circadian outputs that may distinguish the pacemaker in the mammalian suprachiasmatic nucleus (SCN) from peripheral-type oscillators in which the canonical clockworks are similarly regulated in a circadian manner, the rhythmic behavior of the transcriptome in forskolin-stimulated NIH/3T3 fibroblasts was analyzed and compared to that found in the rat SCN in vivo and SCN2.2 cells in vitro. Similar to the scope of circadian gene expression in SCN2.2 cells and the rat SCN, NIH/3T3 fibroblasts exhibited circadian fluctuations in the expression of the core clock genes, Per2, Bmal1 (Mop3), and Cry1 and 323 functionally diverse transcripts (2.6%), many of which were involved in cell communication. Overlap in rhythmically-expressed transcripts among NIH/3T3 fibroblasts, SCN2.2 cells and the rat SCN was limited to these clock genes and four other genes that mediate fatty acid and lipid metabolism or function as nuclear factors. Compared to NIH/3T3 cells, circadian gene expression in SCN oscillators was more prevalent among cellular pathways mediating glucose metabolism and neurotransmission. Coupled with evidence for the rhythmic regulation of the inducible isoform of nitric oxide synthase, the enzyme responsible for the production of nitric oxide, in SCN2.2 cells and the rat SCN but not in fibroblasts, studies examining the effects of a NOS inhibitor on metabolic rhythms in co-cultures containing SCN2.2 cells and untreated NIH/3T3 cells suggest that this gaseous neurotransmitter may play a key role in SCN pacemaker function. Thus, this comparative analysis of circadian gene expression in SCN and non-SCN cells may have important implications in the selective identification of circadian signals involved in the coupling of SCN oscillators and the regulation of rhythmicity in downstream cells or tissues. Keywords: Circadian time course
2006-10-31 | GSE5810 | GEO
Project description:In many organisms, the circadian clock is composed of functionally coupled morning and evening oscillators that regulate the bouts of dawn and dusk activity. In Arabidopsis, oscillator coupling relies on a core loop in which the evening oscillator component TOC1 was proposed to activate a subset of morning-expressed oscillator genes. Our systems-biological approach overturns the current view of the Arabidopsis circadian clock showing that TOC1 does not function as an activator but as a timely-controlled general repressor of morning and evening oscillator components. Repression occurs through rhythmic binding to the promoters of all oscillator genes, suggesting a previously unexpected direct connection between the morning and evening loops.
2012-03-08 | GSE35952 | GEO
Project description:In many organisms, the circadian clock is composed of functionally coupled morning and evening oscillators that regulate the bouts of dawn and dusk activity. In Arabidopsis, oscillator coupling relies on a core loop in which the evening oscillator component TOC1 was proposed to activate a subset of morning-expressed oscillator genes. Our systems-biological approach overturns the current view of the Arabidopsis circadian clock showing that TOC1 does not function as an activator but as a timely-controlled general repressor of morning and evening oscillator components. Repression occurs through rhythmic binding to the promoters of all oscillator genes, suggesting a previously unexpected direct connection between the morning and evening loops. Examination of TOC1 genome-wide binding using TOC1 Minigene (TMG) seedlings expressing the genomic fragment of TOC1 fused to the Yellow Fluorescent Protein in a toc1-2 mutant background (TMG-YFP/toc1-2 seedlings) grown under LD cycles (12h light:12h dark).
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Project description:Circadian clocks are endogenous oscillators that drive organismal metabolism and physiology. Here, we report the first global in vivo quantification of circadian phosphorylation rhythms in mammals. Of more than 20,000 in vivo phosphosites, 25% significantly oscillate in the mouse liver, including novel sites on core clock proteins. Analyzing kinase substrate motifs, we find that the EGF/RAS/ERK pathway is predominantly activated during the day and the AKT/mTOR/p70S6K at night. The extent and amplitude of phosphorylation cycles dominate the rhythms of transcript and protein abundance. A dominant regulatory role for phosphorylation-dependent circadian tuning of signaling pathways allows the organism to rapidly and economically respond to daily changes in nutrient availability and integrate different signaling triggers.
2016-10-18 | PXD003751 | Pride
Project description:In mammals, the suprachiasmatic nucleus (SCN) is the central pacemaker organizing circadian rhythms of behavior and physiology. At the cellular level, the mammalian clock consists of autoregulatory feedback loops involving a set of "clock genes," including the Cryptochrome (Cry) genes, Cry1 and Cry2. Experimental evidence suggests that Cry1 and Cry2 play distinct roles in circadian clock function. In mice, Cry1 is required for sustained circadian rhythms in dissociated SCN neurons or fibroblasts but not in organotypic SCN slices or at the behavioral level, whereas Cry2 is not required at any of these levels. It has been argued that coupling among SCN cellular oscillators compensates for clock gene defects to preserve oscillatory function. Here we test this hypothesis in Cry1(-/-) mice by first disrupting intercellular coupling in vivo using constant light (resulting in behavioral arrhythmicity) and then examining circadian clock gene expression in SCN slices at the single cell level. In this manner, we were able to test the role of intercellular coupling without drugs and while preserving tissue organization, avoiding the confounding influences of more invasive manipulations. Cry1(-/-) mice (as well as control Cry2(-/-) mice) bearing the PER2::LUC knock-in reporter were transferred from a standard light:dark cycle to constant bright light (~650 lux) to induce arrhythmic locomotor patterns. In SCN slices from these animals, we used bioluminescence imaging to monitor PER2::LUC expression in single cells. We show that SCN slices from rhythmic Cry1(-/-) and Cry2(-/-) mice had similarly high percentages of functional single-cell oscillators. In contrast, SCN slices from arrhythmic Cry1(-/-) mice had significantly fewer rhythmic cells than SCN slices from arrhythmic Cry2(-/-) mice. Thus, constant light in vivo disrupted intercellular SCN coupling to reveal a cell-autonomous circadian defect in Cry1(-/-) cells that is normally compensated by intercellular coupling in vivo.
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Project description:Circadian behaviors are regulated by intrinsic biological clocks consisting of central molecular oscillators and output pathways. Despite significant progress in elucidating the central timekeeping mechanisms, the molecular pathways coupling the circadian pacemaker to overt rhythmic behavior and physiology remain elusive. The Drosophila LARK RNA-binding protein is a candidate for such a coupling factor. Previous research indicates that LARK functions downstream of the clock to mediate behavioral outputs. To better understand the roles of LARK in the Drosophila circadian system, we sought to identify RNA molecules associated with LARK in vivo, using a novel strategy that involves capturing the RNA ligands by immunoprecipitation, visualizing the captured RNAs using whole gene microarrays, and identifying functionally relevant targets through genetic screens. Keywords: Association with RNA-binding protein
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