Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology
Ontology highlight
ABSTRACT:
INSTRUMENT(S): LTQ Orbitrap
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Dr. John S O'Neill
PROVIDER: MSV000087673 | MassIVE | Mon Jun 21 05:10:00 BST 2021
REPOSITORIES: MassIVE
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Project description:The daily organisation of most mammalian cellular functions is attributed to circadian regulation of clock-controlled protein expression, driven by daily cycles of CRYPTOCHROME-dependent transcriptional feedback repression. To test this, we used quantitative mass spectrometry to compare wild type and CRY-deficient fibroblasts under constant conditions. In CRY-deficient cells, we found that temporal variation in protein, phosphopeptide, and K+ abundance was at least as great as wild type controls. Most strikingly. the extent of temporal variation within either genotype was much smaller than overall differences in proteome composition between WT and CRY-deficient cells. This proteome imbalance in CRY-deficient cells and tissues was associated with increased susceptibility to proteotoxic stress, which impairs circadian robustness, and may contribute to the wide-ranging phenotypes of CRY-deficient mice. Rather than generating largescale daily variation in proteome composition, we suggest it is plausible that the various transcriptional and post-translational functions of CRY proteins ultimately act to promote protein and osmotic homeostasis against daily perturbation.
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Project description:The cellular landscape of most eukaryotic cells changes dramatically over the course of a 24h day. Whilst the proteome responds directly to daily environmental cycles, it is also regulated by a cellular circadian clock that anticipates the differing demands of day and night. To quantify the relative contribution of diurnal versus circadian regulation, we mapped spatiotemporal proteome dynamics under 12h:12h light:dark cycles compared with constant light. Using Ostreococcus tauri, a prototypical eukaryotic cell, we achieved 85% coverage of the theoretical proteome and provided an unprecedented insight into the identity of proteins that drive and facilitate rhythmic cellular functions. Surprisingly, the overlap between diurnally- and circadian-regulated proteins was quite modest (11%). These proteins exhibited different phases of oscillation between the two conditions, consistent with an interaction between intrinsic and extrinsic regulatory factors. The relative amplitude of rhythmic protein abundance was much lower than would be expected from daily variations in transcript abundance. Transcript rhythmicity was poorly predictive of daily variation in abundance of the encoded protein. We observed coordination between the rhythmic regulation of organelle-encoded proteins with the nuclear-encoded proteins that are targeted to organelles. Rhythmic transmembrane proteins showed a remarkably different phase distribution compared with rhythmic soluble proteins, indicating the existence of a novel circadian regulatory process specific to the biogenesis and/or degradation of membrane proteins. Taken together, our observations argue that the daily spatiotemporal regulation of cellular proteome composition is not dictated solely by clock-regulated gene expression. Instead, it also involves extensive rhythmic post-transcriptional, translational, and post-translational regulation that is further modulated by environmental timing cues.
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Project description:Although costly to maintain, protein homeostasis is indispensable for normal cellular function and long-term health. In mammalian cells and tissues, daily variation in global protein synthesis has been observed, but its utility and consequences for proteome integrity are not fully understood. Using several different pulse-labelling strategies, here we gain direct insight into the relationship between protein synthesis and abundance proteome- wide. We show that protein degradation varies in-phase with protein synthesis, facilitating rhythms in turnover rather than abundance. This results in daily consolidation of proteome renewal whilst minimising changes in composition. Coupled rhythms in synthesis and turnover are especially salient to the assembly of macromolecular protein complexes, particularly the ribosome, the most abundant species of complex in the cell. Daily turnover and proteasomal degradation rhythms render cells and mice more sensitive to proteotoxic stress at specific times of day, potentially contributing to daily rhythms in the efficacy of proteasomal inhibitors against cancer. Our findings suggest that circadian rhythms function to minimise the bioenergetic cost of protein homeostasis through temporal consolidation of protein turnover.
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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
Project description:Natural variation in the consequences of gene overexpression during osmotic stress
| PRJNA939229 | ENA
Project description:Tseng2012 - Circadian clock of N.crassa
A comprehensive model of the circardian clock of fungal Neurospora crassa
, which encompasses existing knowledge of the biochemistry of Neurospora clock, is described by Tseng et al.
(2012). The model is validated against a wide range of experimental phenotypes and has been used to investigate possible molecular explanations of temperature compensation.
This model is described in the article:
Comprehensive modelling of the Neurospora circadian clock and its temperature compensation.
Tseng YY, Hunt SM, Heintzen C, Crosthwaite SK, Schwartz JM
PLoS Comput. Biol. [2012 ; Volume: 8 (Issue: 3 )] Page info: e1002437
Abstract:
Circadian clocks provide an internal measure of external time allowing organisms to anticipate and exploit predictable daily changes in the environment. Rhythms driven by circadian clocks have a temperature compensated periodicity of approximately 24 hours that persists in constant conditions and can be reset by environmental time cues. Computational modelling has aided our understanding of the molecular mechanisms of circadian clocks, nevertheless it remains a major challenge to integrate the large number of clock components and their interactions into a single, comprehensive model that is able to account for the full breadth of clock phenotypes. Here we present a comprehensive dynamic model of the Neurospora crassa circadian clock that incorporates its key components and their transcriptional and post-transcriptional regulation. The model accounts for a wide range of clock characteristics including: a periodicity of 21.6 hours, persistent oscillation in constant conditions, arrhythmicity in constant light, resetting by brief light pulses, and entrainment to full photoperiods. Crucial components influencing the period and amplitude of oscillations were identified by control analysis. Furthermore, simulations enabled us to propose a mechanism for temperature compensation, which is achieved by simultaneously increasing the translation of frq RNA and decreasing the nuclear import of FRQ protein.
Figure 3 of the reference publication has been reproduced using Copasi 4.8 (Build 35).
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2024-09-02 | BIOMD0000000437 | BioModels
Project description:Natural variation in the consequences of gene overexpression during osmotic stress [RNA-Seq]
| PRJNA939230 | ENA
Project description:Natural variation in the consequences of gene overexpression during osmotic stress [BAR-Seq]
| PRJNA939234 | ENA
Project description:In mammals, temporally coordinated daily rhythms of behaviour and physiology are generated by a multi-oscillatory circadian system, entrained through cyclic environmental cues (e.g. light). Presence of niche-dependent physiological time cues have been proposed to allow local tissues flexibility of adopting a different phase relationship if circumstances require. Up till now, such tissue-unique stimuli have remained elusive. Here we show that cycles of mechanical loading and osmotic stimuli within physiological range drive rhythmic expression of clock genes and reset clock phase and amplitude in cartilage and intervertebral disc tissues.
2023-05-19 | E-MTAB-11040 | biostudies-arrayexpress
Project description:This the single cell model from the article:
A multiscale model to investigate circadian rhythmicity of pacemaker neurons in the suprachiasmatic nucleus.
Vasalou C, Henson MA. PLoS Comput Biol
2010 Mar 12;6(3):e1000706.
PMID: 20300645
, DOI: 10.1371/journal.pcbi.1000706
;
Abstract:
The suprachiasmatic nucleus (SCN) of the hypothalamus is a multicellular system that drives daily rhythms in mammalian behavior and physiology. Although the gene regulatory network that produces daily oscillations within individual neurons is well characterized, less is known about the electrophysiology of the SCN cells and how firing rate correlates with circadian gene expression. We developed a firing rate code model to incorporate known electrophysiological properties of SCN pacemaker cells, including circadian dependent changes in membrane voltage and ion conductances. Calcium dynamics were included in the model as the putative link between electrical firing and gene expression. Individual ion currents exhibited oscillatory patterns matching experimental data both in current levels and phase relationships. VIP and GABA neurotransmitters, which encode synaptic signals across the SCN, were found to play critical roles in daily oscillations of membrane excitability and gene expression. Blocking various mechanisms of intracellular calcium accumulation by simulated pharmacological agents (nimodipine, IP3- and ryanodine-blockers) reproduced experimentally observed trends in firing rate dynamics and core-clock gene transcription. The intracellular calcium concentration was shown to regulate diverse circadian processes such as firing frequency, gene expression and system periodicity. The model predicted a direct relationship between firing frequency and gene expression amplitudes, demonstrated the importance of intracellular pathways for single cell behavior and provided a novel multiscale framework which captured characteristics of the SCN at both the electrophysiological and gene regulatory levels.
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2024-09-02 | BIOMD0000000246 | BioModels