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Rhythmic glucose metabolism regulates the redox circadian clockwork in human red blood cells (LC-MS)

ABSTRACT:

Circadian clocks coordinate mammalian behaviour and physiology enabling organisms to anticipate 24-hour cycles. Transcription-translation feedback loops are thought to drive these clocks in most of mammalian cells. However, red blood cells (RBCs), which do not contain a nucleus, and cannot perform transcription or translation, nonetheless exhibit circadian redox rhythms. Here we show human RBCs display circadian regulation of glucose metabolism, which is required to sustain daily redox oscillations. We found daily rhythms of metabolite levels and flux through glycolysis and the pentose phosphate pathway (PPP). We show that inhibition of critical enzymes in either pathway abolished 24-hour rhythms in metabolic flux and redox oscillations, and determined that metabolic oscillations are necessary for redox rhythmicity. Furthermore, metabolic flux rhythms also occur in nucleated cells, and persist when the core transcriptional circadian clockwork is absent in Bmal1 knockouts. Thus, we propose that rhythmic glucose metabolism is an integral process in circadian rhythms.

LC-MS assay protocols and data are reported in the current study MTBLS1285.

GC-MS assay protocols and data for this study are reported in MTBLS1286.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic

SUBMITTER: Ratnasekhar Ch

PROVIDER: MTBLS1285 | MetaboLights | 2020-11-13

REPOSITORIES: MetaboLights

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Rhythmic glucose metabolism regulates the redox circadian clockwork in human red blood cells (GC-MS)

Project description:Circadian clocks coordinate mammalian behaviour and physiology enabling organisms to anticipate 24-hour cycles. Transcription-translation feedback loops are thought to drive these clocks in most of mammalian cells. However, red blood cells (RBCs), which do not contain a nucleus, and cannot perform transcription or translation, nonetheless exhibit circadian redox rhythms. Here we show human RBCs display circadian regulation of glucose metabolism, which is required to sustain daily redox oscillations. We found daily rhythms of metabolite levels and flux through glycolysis and the pentose phosphate pathway (PPP). We show that inhibition of critical enzymes in either pathway abolished 24-hour rhythms in metabolic flux and redox oscillations, and determined that metabolic oscillations are necessary for redox rhythmicity. Furthermore, metabolic flux rhythms also occur in nucleated cells, and persist when the core transcriptional circadian clockwork is absent in Bmal1 knockouts. Thus, we propose that rhythmic glucose metabolism is an integral process in circadian rhythms. GC-MS assay protocols and data are reported in the current study MTBLS1286.LC-MS assay protocols and data for this study are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1285' rel='noopener noreferrer' target='_blank'>MTBLS1285</a>.

2020-11-13 | MTBLS1286 | MetaboLights

Carbon monoxide metabolism is essential for circadian transcription and dynamics

Project description:Circadian clocks are cell-autonomous oscillators regulating daily rhythms in a wide range of physiological, metabolic and behavioral processes. Conversely, metabolic signals such as redox state, NAD+/NADH and AMP/ADP ratios or heme feed back to and modulate circadian mechanisms to optimize energy utilization across the 24-hour cycle. We show that the signaling molecule carbon monoxide (CO) generated by rhythmic heme degradation is required for normal circadian rhythms as well as circadian metabolic outputs. CO suppresses circadian transcription by attenuating CLOCK/BMAL1 binding to target promoters. Pharmacological inhibition or genetic depletion of CO-producing heme oxygenases abrogate normal daily cycles in mammalian cells and Drosophila. In mouse hepatocytes, suppression of CO production leads to a global upregulation of CLOCK/BMAL1-dependent circadian gene expression and thereby misregulation of many metabolic processes including gluconeogenesis.

2016-10-05 | GSE55448 | GEO

Non-canonical circadian oscillations in Drosophila S2 cells

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

Twenty-four hour rhythms in the absence of the clock gene Bmal1

Project description:Circadian (~24 hour) clocks exist in almost all types of living organism and play a fundamental role in regulating daily physiological and behavioural processes. The transcription factor BMAL1 (ARNTL) is thought to be one of the principal drivers of the molecular clock in mammals since its deletion abolishes 24-hour activity patterning, an important physiological output of the clockwork. However, whether or not Bmal1-/- mice can nevertheless display molecular 24-hour rhythms is unknown. Here, we determined whether Bmal1 function is necessary for daily molecular oscillations in two tissues – skin fibroblasts and liver. Unexpectedly, both tissues exhibited robust 24-hour oscillations over 2-3 days in the absence of any exogenous synchronizers such as daily light or temperature cycles. This demonstrates a competent 24-hour molecular pacemaker in Bmal1 knockouts. Indeed, molecular oscillations were pervasive throughout the transcriptome, proteome and phosphoproteome of Bmal1-/- mice. In particular, several proteins exhibited rhythmic phosphorylation in both Bmal1-proficient and -deficient cells, highlighting an unanticipated role for post-translational regulators in 24-hour rhythms in the absence of any known clock mechanisms.

2020-02-17 | PXD009243 | Pride

The pentose phosphate pathway regulates the circadian clock

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.

2016-08-18 | GSE74439 | GEO

Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks

Project description:Daily rhythms in mammalian behaviour and physiology are generated by a multi-oscillator circadian system entrained through environmental cues (e.g. light and feeding). The presence of tissue niche-dependent physiological time cues has been proposed, allowing tissues the ability of circadian phase adjustment based on local signals. However, to date, such stimuli have remained elusive. Here we show that daily patterns of mechanical loading and associated osmotic challenge within physiological ranges reset circadian clock phase and amplitude in cartilage and intervertebral disc tissues in vivo and in tissue explant cultures. Hyperosmolarity (but not hypo-osmolarity) resets clocks in young and ageing skeletal tissues and induce genome-wide expression of rhythmic genes in cells. Mechanistically, RNAseq and biochemical analysis revealed the PLD2-mTORC2-AKT-GSK3β axis as a convergent pathway for both in vivo loading and hyperosmolarity-induced clock changes. These results reveal diurnal patterns of mechanical loading and consequent daily surges in osmolarity as a bona fide tissue niche-specific time cue to maintain skeletal circadian rhythms in sync.

2023-08-17 | E-MTAB-12877 | biostudies-arrayexpress

Metabolic oscillations on the circadian time scale in Drosophila cells lacking clock genes

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

Clock genes in human oral mucosa

Project description:Circadian rhythms are daily oscillations of multiple biological processes driven by endogenous clocks. Imbalance of these rhythms has been associated with cancerogenesis in humans. To further elucidate the role of the circadian clock in cellular growth control, tumor suppression and cancer treatment, a standard of circadian gene regulations in healthy men is essential. Comparative microarray analyses were conducted investigating the relative mRNA expression of clock genes throughout a 24-hour period in biopsies obtained from oral mucosa of eight healthy diurnally active male study participants. A custom-designed oligo-based microarray which in addition to oncogenes and inflammatory genes contains probes for 20 clock genes and 70 clock-associated genes in human was used. Keywords: Human gene expression study

2010-05-17 | GSE11469 | GEO

Conservation of primordial ~12-hour ultradian gene programs in humans

Project description:Biological rhythms have important implications for human disease, as evidenced by the effects of disrupting the 24h circadian clock. While circadian rhythms are entrained to the once daily light-dark cycle of the sun, coastal marine organisms are known to exhibit 12h ultradian rhythms, corresponding to the twice daily movement of the tides. Human ancestors emerged from a circa-tidal environment millions of years ago. However, whether 12h ultradian rhythms are conserved in humans remains unknown. Here, we performed prospective, high temporal resolution transcriptome profiling in the peripheral white blood cells of three healthy subjects. Remarkably, all three subjects exhibited a shared transcriptional program demonstrating robust ~12h rhythms. Pathway analysis implicated 12h transcriptional oscillations primarily affected core cellular processes, including RNA and protein metabolism, with strong homology to the 12h gene programs previously identified in cnidarian marine species. These results establish the existence of 12h biological rhythms in humans. Such rhythms appear to have a primordial evolutionary origin dating back at least 700 million years and are likely to have far-reaching implications in human health and disease.

2023-08-07 | GSE220120 | GEO

Circadian Rhythms in Bmal1-/- Mouse Fibroblast Cells and Liver Tissue

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.

2020-02-14 | GSE111696 | GEO

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