Space-time logic of liver gene expression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE145197 | GEO | 2020/11/01
REPOSITORIES: GEO
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Project description:Space-time logic of liver gene expression
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Project description:Circadian clocks drive 24-h rhythms of physiology and behavior. The circadian clock of hepatocytes has been shown to regulate glucose metabolism, and we were interested if rescuing liver clock function can reverse metabolic impairments in hyperphagic/obese Clock-D19 mutant mice. We compared transcripomte regulation in livers (at Zeitgeber time ZT10) of wild-type (C57BL/6J) and Clock-D19 mice and Clock-D19 mice with genetic rescue of liver clock function using hydrodynamic tail vein injection of a WT-CLOCK expression plasmid
2017-03-31 | GSE94838 | GEO
Project description:Most cells in the body contain a cell autonomous molecular clock, but the requirement of peripheral clocks for circadian rhythmicity, and their effects on physiology, are not well understood. Here we show that deletion of core clock components REV-ERBa and b in adult mouse hepatocytes caused the loss of circadian rhythmicity of many liver genes, as expected, but also led to maintained and even gained rhythmicity of other genes without altering feeding behavior. The loss of REV-ERBs from hepatocytes leads to an exaggerated circadian rhythm of de novo lipogenesis and serum triglyceride levels. It is increasingly recognized that liver function is also influenced by non-hepatocytic cells, and remarkably the loss of REV-ERBs in hepatocytes remodeled the circadian transcriptomes of multiple cell types within the liver without altering their core clocks, indicating that hepatocytes communicated time signals to the non-hepatocytic cells. Finally, alteration of food availability, which is the dominant zeitgeber in the liver, demonstrated strong interdependence of the cell-autonomous hepatocyte clock mechanism and non-cell-autonomous environmental change. Together these studies reveal the interdependence of endogenous hepatocyte clocks and feeding entrainment on the regulation of circadian rhythms of multiple cell types in the liver.
2020-07-30 | GSE143526 | GEO
Project description:Most cells in the body contain a cell autonomous molecular clock, but the requirement of peripheral clocks for circadian rhythmicity, and their effects on physiology, are not well understood. Here we show that deletion of core clock components REV-ERBa and b in adult mouse hepatocytes caused the loss of circadian rhythmicity of many liver genes, as expected, but also led to maintained and even gained rhythmicity of other genes without altering feeding behavior. The loss of REV-ERBs from hepatocytes leads to an exaggerated circadian rhythm of de novo lipogenesis and serum triglyceride levels. It is increasingly recognized that liver function is also influenced by non-hepatocytic cells, and remarkably the loss of REV-ERBs in hepatocytes remodeled the circadian transcriptomes of multiple cell types within the liver without altering their core clocks, indicating that hepatocytes communicated time signals to the non-hepatocytic cells. Finally, alteration of food availability, which is the dominant zeitgeber in the liver, demonstrated strong interdependence of the cell-autonomous hepatocyte clock mechanism and non-cell-autonomous environmental change. Together these studies reveal the interdependence of endogenous hepatocyte clocks and feeding entrainment on the regulation of circadian rhythms of multiple cell types in the liver.
2020-07-30 | GSE143525 | GEO
Project description:Most cells in the body contain a cell autonomous molecular clock, but the requirement of peripheral clocks for circadian rhythmicity, and their effects on physiology, are not well understood. Here we show that deletion of core clock components REV-ERBa and b in adult mouse hepatocytes caused the loss of circadian rhythmicity of many liver genes, as expected, but also led to maintained and even gained rhythmicity of other genes without altering feeding behavior. The loss of REV-ERBs from hepatocytes leads to an exaggerated circadian rhythm of de novo lipogenesis and serum triglyceride levels. It is increasingly recognized that liver function is also influenced by non-hepatocytic cells, and remarkably the loss of REV-ERBs in hepatocytes remodeled the circadian transcriptomes of multiple cell types within the liver without altering their core clocks, indicating that hepatocytes communicated time signals to the non-hepatocytic cells. Finally, alteration of food availability, which is the dominant zeitgeber in the liver, demonstrated strong interdependence of the cell-autonomous hepatocyte clock mechanism and non-cell-autonomous environmental change. Together these studies reveal the interdependence of endogenous hepatocyte clocks and feeding entrainment on the regulation of circadian rhythms of multiple cell types in the liver.
2020-07-30 | GSE143524 | GEO
Project description:Circadian clocks coordinate time-of-day specific metabolic and physiological processes to maximize performance and fitness. In addition to light, which is considered the strongest time cue to entrain animal circadian clocks, metabolic input has emerged as an important signal for clock modulation and entrainment, especially in peripheral clocks. Circadian clock proteins have been to be substrates of O-GlcNAcylation, a nutrient sensitive post-translational modification (PTM), and the interplay between clock protein O-GlcNAcylation and other PTMs, like phosphorylation, is expected to facilitate the regulation of circadian physiology by metabolic signals. Here, we used mass spectrometry proteomics to identify PTMs on PERIOD, the key biochemical timer of the Drosophila clock, over the circadian cycle.
2017-11-23 | MSV000081736 | MassIVE
Project description:Various aspects of physiology and cell function present self-sustained ~24h variations termed circadian rhythms, enabling anticipation and adaptation to the 24-h cycle produced by the Earth’s rotation. The circadian clock system consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus, and peripheral clocks present in distinct tissues. In particular, peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis. Here, we established and characterized a human hepatocyte in vitro system in which human primary hepatocytes displayed self-sustained oscillations independently of external cues a distinguishing feature of circadian clocks. We then used this experimental system to study the impact of circadian oscillations in human liver pathophysiology. By generating hepatocyte circadian transcriptomes, we demonstrated that the transcriptional state of cultured human hepatocytes is dynamic across 24h. Analyses of gene expression data identified a set of cycling genes, including a subset of well-established ‘core clock genes’ and oscillating genes related to inflammation, drug metabolism, and energy homeostasis. We documented a circadian-dependent induction of the pro-inflammatory cytokines IL-1b, IL-6, TNF-a CXCLl1 and CXCL10 triggered by LPS or IFN-b in human hepatocytes. We also demonstrated circadian fluctuations of a subset of drug metabolism enzymes, which regulate drug pharmacokinetics. Among these enzymes, we identified CYP3A4, as one displaying circadian fluctuations at activity levels and a time-dependent induction with rifampin. Finally, we showed the impact of applying chronopharmacotherapy by designing a treatment protocol to minimize atorvastatin and acetaminophen induced hepatotoxicity. Collectively, our findings document that circadian time can influence the magnitude of the inflammatory response in the liver and the efficacy, toxicity, and/or the therapeutic index of drugs.
2024-02-28 | GSE218243 | GEO
Project description:Various aspects of physiology and cell function present self-sustained ~24h variations termed circadian rhythms, enabling anticipation and adaptation to the 24-h cycle produced by the Earth’s rotation. The circadian clock system consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus, and peripheral clocks present in distinct tissues. In particular, peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis. Here, we established and characterized a human hepatocyte in vitro system in which human primary hepatocytes displayed self-sustained oscillations independently of external cues a distinguishing feature of circadian clocks. We then used this experimental system to study the impact of circadian oscillations in human liver pathophysiology. By generating hepatocyte circadian transcriptomes, we demonstrated that the transcriptional state of cultured human hepatocytes is dynamic across 24h. Analyses of gene expression data identified a set of cycling genes, including a subset of well-established ‘core clock genes’ and oscillating genes related to inflammation, drug metabolism, and energy homeostasis. We documented a circadian-dependent induction of the pro-inflammatory cytokines IL-1b, IL-6, TNF-a CXCLl1 and CXCL10 triggered by LPS or IFN-b in human hepatocytes. We also demonstrated circadian fluctuations of a subset of drug metabolism enzymes, which regulate drug pharmacokinetics. Among these enzymes, we identified CYP3A4, as one displaying circadian fluctuations at activity levels and a time-dependent induction with rifampin. Finally, we showed the impact of applying chronopharmacotherapy by designing a treatment protocol to minimize atorvastatin and acetaminophen induced hepatotoxicity. Collectively, our findings document that circadian time can influence the magnitude of the inflammatory response in the liver and the efficacy, toxicity, and/or the therapeutic index of drugs.
2024-02-28 | GSE218242 | GEO
Project description:The circadian clock represents an evolutionarily acquired gene network that synchronizes physiology to anticipate environmental changes caused by the succession of day and night. While most mammalian cells have a circadian clock, their synchronization depends on a central pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus that integrates light signals. While peripheral organs can be also synchronized by feeding cues and can be uncoupled from the central pacemaker, no impact of peripheral organs on the central clock has been yet observed. Here, we used a mouse chimeric model in which mouse hepatocytes have been replaced by human hepatocytes that have different circadian and signaling properties to characterize such potential feedback. Remarkably, we observed that liver humanization rewired the liver diurnal gene expression and advance the circadian clock by approximately 4 hours. Strikingly, this phase advance was also observed in the muscle and for the entire rhythmic physiology of the animals, with an impact of human hepatocytes on the circadian function of the central clock. Like mice with a deficient central clock, the humanized animals shifted their physiology more rapidly to the light phase under day feeding. This data prompt to reconsider the role of peripheral clocks on the central pacemaker and offers new perspective to understand the impact of diseased organs on the global circadian physiology.
2023-05-25 | GSE212079 | GEO
Project description:The circadian clock drives the oscillatory expression of thousands of genes across all tissues and bears significant implications for human health. RNA-seq time-series experiments interrogate the mechanistic links between transcriptional rhythms and phenotypic outcomes. Analysis methods must overcome the challenges of sparse temporal sampling, noisy data, and non-strictly periodic dynamics. Moreover, there remains a need for differential cycling analysis methods that can identify complex changes in rhythmicity for 2-sample comparisons across experimental conditions. We present TimeChange -- a non-parametric and model-free method for the quantification of differential dynamics across experimental conditions. The method leverages a data transformation technique known as time-delay embedding to reconstruct the underlying state space for each gene-of-interest. Takens’ embedding theorem implies that rhythmic dynamics will exhibit circular patterns in the embedded space. TimeChange non-parametrically compares the distributions of points in the embedded space via the Fasano-Franceschini test to assess whether the topological structures differ significantly between phenotypes, thereby quantifying differences in transcriptional dynamics without requiring knowledge of the underlying model. Application of TimeChange to synthetic data shows that it accurately identifies changes in transcriptomic dynamics, including differences in amplitude/peaked-ness; changes in sawtooth asymmetries; and trending oscillatory drifts (e.g. linear, damped, and contractile). We further show that the method has potential utility beyond circadian dynamics. For instance, initial tests of TimeChange using erg rowing-machine data shows accurate classification of differential stroke dynamics in real time, suggesting potential uses of TimeChange in the field of sports science and medicine.
2023-06-30 | GSE193991 | GEO