The hepatocyte insulin receptor is required to program rhythmic gene expression and the liver clock
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PROVIDER: PRJNA693441 | ENA |
REPOSITORIES: ENA
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Project description:Rhythmic intraorgan communication coordinates environmental signals and cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific knockout of core components of the molecular clock, Rev-erba and b (ReverbhDKO), alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in non-parenchymal cells (NPC) of the liver. Here we report that in diet induced obesity (DIO)-caused fatty liver, hepatocyte SREBP cleavage-activating protein (SCAP) is required for ReverbhDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in Kupffer cells (KC). Integrative analyses of isolated hepatocytes and Kupffer cells uncovered potential signals, including secreted polypeptides and metabolites, that gain rhythmicity in the absence of REV-ERBs in a SCAP-dependent manner. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in DIO and fatty liver disease.
2023-04-04 | GSE206318 | GEO
Project description:Rhythmic intraorgan communication coordinates environmental signals and cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific knockout of core components of the molecular clock, Rev-erba and b (ReverbhDKO), alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in non-parenchymal cells (NPC) of the liver. Here we report that in diet induced obesity (DIO)-caused fatty liver, hepatocyte SREBP cleavage-activating protein (SCAP) is required for ReverbhDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in Kupffer cells (KC). Integrative analyses of isolated hepatocytes and Kupffer cells uncovered potential signals, including secreted polypeptides and metabolites, that gain rhythmicity in the absence of REV-ERBs in a SCAP-dependent manner. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in DIO and fatty liver disease.
2023-04-04 | GSE206317 | GEO
Project description:Rhythmic intraorgan communication coordinates environmental signals and cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific knockout of core components of the molecular clock, Rev-erba and b (ReverbhDKO), alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in non-parenchymal cells (NPC) of the liver. Here we report that in diet induced obesity (DIO)-caused fatty liver, hepatocyte SREBP cleavage-activating protein (SCAP) is required for ReverbhDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in Kupffer cells (KC). Integrative analyses of isolated hepatocytes and Kupffer cells uncovered potential signals, including secreted polypeptides and metabolites, that gain rhythmicity in the absence of REV-ERBs in a SCAP-dependent manner. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in DIO and fatty liver disease.
2023-04-04 | GSE206316 | GEO
Project description:Evolutionary conserved biological rhythms play a fundamental role in the physiology and behavior of all light-sensitive organisms. Generation of rhythmic expression of clock-controlled genes is orchestrated by a molecular circadian clock constitutes by interconnected negative feedback loops of transcription factors. In this study, we want to characterize gene which also present a rhythmic translation through the characterization of genes with a rhythmic polysomal/total RNA ratio. Analyze of gene expression in liver total RNA and polysomal RNA harvested every 2 hrs during 2 series of 48 hrs, 2 mice per samples
2012-12-01 | E-GEOD-33726 | biostudies-arrayexpress
Project description:Virtually every mammalian tissue exhibits rhythmic expression in thousands of genes, which activate tissue-specific processes at appropriate times of the day. Much of this rhythmic expression is thought to be driven cell-autonomously by molecular circadian clocks present throughout the body. However, increasing evidence suggests that systemic signals, and more specifically rhythmic food intake (RFI), can regulate rhythmic gene expression independently of the circadian clock. To determine the relative contribution of cell autonomous clocks versus RFI in the regulation of rhythmic gene expression, we developed a system that allows long-term manipulation of the daily rhythm of food intake in the mouse, and analyzed liver gene expression by RNA-Seq in mice fed ad libitum, only at night, or arrhythmically (mouse eating 1/8th of their daily food intake every 3 hours). We show that 70% of the cycling mouse liver transcriptome loses rhythmicity under arrhythmic feeding. Remarkably, this loss of rhythmic gene expression under arrhythmic feeding is independent of the liver circadian clock, which continues to exhibit normal oscillations in core clock gene expression. Many genes that lose rhythmicity participate in the regulation of metabolic processes such as lipogenesis and glycogenesis, likely contributing to an increased sensitivity to insulin that was observed in arrhythmically-fed mice. We also show that night-restricted feeding significantly increases the number of rhythmically expressed genes as well as the amplitude of the rhythms. Together, these results indicate that metabolic transcription factors control a large fraction of the rhythmic mouse liver transcriptome, and demonstrate that systemic signals driven by rhythmic food intake play a more important role than the cell-autonomous circadian clock in driving rhythms in liver gene expression and metabolic functions.
2019-04-25 | GSE118967 | GEO
Project description:Diurnal oscillations of gene expression controlled by the circadian clock underlie rhythmic physiology across most living organisms. Although such rhythms have been extensively studied at the level of transcription and mRNA accumulation, little is known about the accumulation patterns of proteins. Here, we quantified temporal profiles in the murine hepatic proteome under physiological light–dark conditions using stable isotope labeling by amino acids quantitative MS. To measure the daily accumulation of proteins, we designed an SILAC MS experiment, in which total protein extracts were harvested from C57BL/6J mice every 3 h for 2 d (eight samples per day). Relative protein abundance in each of 16 samples was quantified against a common reference sample labeled using the SILAC method. The generated mass spectra allowed the identification of a total of 5,827 distinct proteins, of which 70% yielded relative measurements in at least 8 of 16 samples. Our analysis identified over 5,000 proteins, of which several hundred showed robust diurnal oscillations with peak phases enriched in the morning and during the night and related to core hepatic physiological functions. Combined mathematical modeling of temporal protein and mRNA profiles indicated that proteins accumulate with reduced amplitudes and significant delays, consistent with protein half-life data. Moreover, a group comprising about one-half of the rhythmic proteins showed no corresponding rhythmic mRNAs, indicating significant translational or posttranslational diurnal control. Such rhythms were highly enriched in secreted proteins accumulating tightly during the night. Also, these rhythms persisted in clock-deficient animals subjected to rhythmic feeding, suggesting that food-related entrainment signals influence rhythms in circulating plasma factors
2014-08-08 | PXD001211 | Pride
Project description:The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) that synchronizes self-sustained oscillators in most peripheral cells. Rhythmic gene expression in peripheral tissues can be driven by cyclic systemic cues emanating from the SCN or by local oscillators. To discriminate between these two mechanisms, we engineered a mouse strain with a conditionally active liver clock. Transcriptome profiling revealed that the circadian transcription of most genes depends on functional hepatocyte clocks. However, the expression of 31 genes, including mPer2, oscillates robustly in clock-arrested hepatocytes. Such genes may be implicated in the synchronization of liver oscillators
2006-12-30 | E-MEXP-842 | biostudies-arrayexpress
Project description:Mammalian gene expression displays widespread circadian oscillations. Rhythmic transcription underlies the core clock mechanism, but it cannot explain numerous observations made at the level of protein rhythmicity. We have used ribosome profiling in mouse liver to measure the translation of mRNAs into protein around-the-clock and at high temporal and nucleotide resolution. Transcriptome-wide, we discovered extensive rhythms in ribosome occupancy, and identified a core set of ≈150 mRNAs subject to particularly robust daily changes in translation efficiency. Cycling proteins produced from non-oscillating transcripts revealed thus far unknown rhythmic regulation associated with specific pathways (notably in iron metabolism, through the rhythmic translation of transcripts containing iron responsive elements), and indicated feedback to the rhythmic transcriptome through novel rhythmic transcription factors. Moreover, estimates of relative levels of core clock protein biosynthesis that we deduced from the data explained known features of the circadian clock better than did mRNA expression alone. Finally, we identified uORF translation as a novel regulatory mechanism within the clock circuitry. Consistent with the occurrence of translated uORFs in several core clock transcripts, loss-of-function of Denr, a known regulator of re-initiation after uORF usage and of ribosome recycling, led to circadian period shortening in cells. In summary, our data offer a framework for understanding the dynamics of translational regulation, circadian gene expression, and metabolic control in a solid mammalian organ.
2015-10-14 | GSE67305 | GEO
Project description:Reprogramming of rhythmic liver metabolism by intestine clock
| PRJNA911767 | ENA
Project description:The circadian regulation of transcriptional processes has a broad impact on cell metabolism. Here, we compared the diurnal transcriptome of human skeletal muscle conducted on serial muscle biopsies in vivo with profiles of human skeletal myotubes synchronized in vitro. Extensive rhythmic transcription was observed in human skeletal muscle in comparison to in vitro cell culture. However, nearly half of the in vivo rhythmicity was lost at the mRNA accumulation level. siRNA-mediated clock disruption in primary myotubes significantly affected the expression of ~8% of all genes, with impact on glucose homeostasis and lipid metabolism. Genes involved in GLUT4 expression, translocation and recycling were negatively affected, whereas lipid metabolic genes were altered to promote activation of lipid utilization. Moreover, basal and insulin stimulated glucose uptake were significantly reduced upon CLOCK depletion. Altogether, our findings suggest an essential role for cell-autonomous circadian clocks in coordinating muscle glucose homeostasis and lipid metabolism in humans.
2018-04-16 | GSE108539 | GEO