Out of breath, out of time: interactions between HIF and circadian rhythms

2020 ◽  
Vol 319 (3) ◽  
pp. C533-C540
Author(s):  
Emma J. O’Connell ◽  
Chloe-Anne Martinez ◽  
Yichuan G. Liang ◽  
Peter A. Cistulli ◽  
Kristina M. Cook
Keyword(s):  
Circadian Clock ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Cellular Level ◽  
The Body ◽  
Circadian Clocks ◽  
Molecular Clocks ◽  
Circadian Transcription ◽  
New Strategies

Humans have internal circadian clocks that ensure that important physiological functions occur at specific times of the day. These molecular clocks are regulated at the genomic level and exist in most cells of the body. Multiple circadian resetting cues have been identified, including light, temperature, and food. Recently, oxygen has been identified as a resetting cue, and emerging science indicates that this occurs through interactions at the cellular level between the circadian transcription-translation feedback loop and the hypoxia-inducible pathway (hypoxia-inducible factor; subject of the 2019 Nobel Prize in Physiology or Medicine). This review will cover recently identified relationships between HIF and proteins of the circadian clock. Interactions between the circadian clock and hypoxia could have wide-reaching implications for human diseases, and understanding the molecular mechanisms regulating these overlapping pathways may open up new strategies for drug discovery.

scholarly journals Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1263
Author(s):  
Lamis Saad ◽  
Jean Zwiller ◽  
Andries Kalsbeek ◽  
Patrick Anglard
Keyword(s):  
Circadian Clock ◽  
Drug Addiction ◽  
Epigenetic Regulation ◽  
Molecular Mechanisms ◽  
Feedback System ◽  
Circadian Clocks ◽  
Shift Workers ◽  
Timing System ◽  
Small Regulatory Rnas ◽  
Circadian Timing System

Based on studies describing an increased prevalence of addictive behaviours in several rare sleep disorders and shift workers, a relationship between circadian rhythms and addiction has been hinted for more than a decade. Although circadian rhythm alterations and molecular mechanisms associated with neuropsychiatric conditions are an area of active investigation, success is limited so far, and further investigations are required. Thus, even though compelling evidence connects the circadian clock to addictive behaviour and vice-versa, yet the functional mechanism behind this interaction remains largely unknown. At the molecular level, multiple mechanisms have been proposed to link the circadian timing system to addiction. The molecular mechanism of the circadian clock consists of a transcriptional/translational feedback system, with several regulatory loops, that are also intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape shows profound changes in the addictive brain, with significant alterations in histone modification, DNA methylation, and small regulatory RNAs. The combination of these two observations raises the possibility that epigenetic regulation is a common plot linking the circadian clocks with addiction, though very little evidence has been reported to date. This review provides an elaborate overview of the circadian system and its involvement in addiction, and we hypothesise a possible connection at the epigenetic level that could further link them. Therefore, we think this review may further improve our understanding of the etiology or/and pathology of psychiatric disorders related to drug addiction.

scholarly journals The sweet tooth of the circadian clock

2017 ◽  
Vol 45 (4) ◽  
pp. 871-884 ◽  
Author(s):  
Minnie Fu ◽  
Xiaoyong Yang
Keyword(s):  
Circadian Clock ◽  
Metabolic Response ◽  
Circadian Clocks ◽  
Molecular Clocks ◽  
Post Translational Modifications ◽  
The Core ◽  
Input And Output ◽  
Intracellular Proteins ◽  
Translational Mechanisms

The endogenous circadian clock is a key regulator of daily metabolic processes. On the other hand, circadian clocks in a broad range of tissues can be tuned by extrinsic and intrinsic metabolic cues. The bidirectional interaction between circadian clocks and metabolism involves both transcriptional and post-translational mechanisms. Nuclear receptors exemplify the transcriptional programs that couple molecular clocks to metabolism. The post-translational modifications of the core clock machinery are known to play a key role in metabolic entrainment of circadian clocks. O-linked N-acetylglucosamine modification (O-GlcNAcylation) of intracellular proteins is a key mediator of metabolic response to nutrient availability. This review highlights our current understanding of the role of protein O-GlcNAcylation in mediating metabolic input and output of the circadian clock.

Two-Photon Imaging of Cellular Activities in Oxygen Sensing Tissues

2008 ◽  
Vol 14 (6) ◽  
pp. 519-525 ◽  
Author(s):  
Christoph Wotzlaw ◽  
Utta Berchner-Pfannschmidt ◽  
Joachim Fandrey ◽  
Helmut Acker
Keyword(s):  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Oxygen Sensing ◽  
Rat Kidney ◽  
Hypoxia Inducible Factor ◽  
The Body ◽  
Cellular Functions ◽  
Protein Protein Interaction ◽  
Two Photon

AbstractThe cellular oxygen sensing system of the body ensures appropriate adaptation of cellular functions toward hypoxia by regulating gene expression and ion channel activity. Two-photon laser microscopy is an ideal tool to study and prove the relevance of the molecular mechanisms within oxygen sensing pathways on the cellular and complex tissue or organ level. Images of hypoxia inducible factor 1 (HIF-1) subunit nuclear mobility and protein-protein interaction in living cells, of hypoxia-induced changes in membrane potential and intracellular calcium of live ex vivo carotid bodies as well as of rat kidney proximal tubulus function in vivo, will be shown.

scholarly journals A dual-feedback loop model of the mammalian circadian clock for multi-input control of circadian phase

2020 ◽  
Vol 16 (11) ◽  
pp. e1008459
Author(s):  
Lindsey S. Brown ◽  
Francis J. Doyle
Keyword(s):  
Circadian Clock ◽  
Small Molecules ◽  
Feedback Loop ◽  
Feedback Loops ◽  
The Body ◽  
Loop Model ◽  
Circadian Phase ◽  
Input Control ◽  
Cellular Components

The molecular circadian clock is driven by interlocked transcriptional-translational feedback loops, producing oscillations in the expressions of genes and proteins to coordinate the timing of biological processes throughout the body. Modeling this system gives insight into the underlying processes driving oscillations in an activator-repressor architecture and allows us to make predictions about how to manipulate these oscillations. The knockdown or upregulation of different cellular components using small molecules can disrupt these rhythms, causing a phase shift, and we aim to determine the dosing of such molecules with a model-based control strategy. Mathematical models allow us to predict the phase response of the circadian clock to these interventions and time them appropriately but only if the model has enough physiological detail to describe these responses while maintaining enough simplicity for online optimization. We build a control-relevant, physiologically-based model of the two main feedback loops of the mammalian molecular clock, which provides sufficient detail to consider multi-input control. Our model captures experimentally observed peak to trough ratios, relative abundances, and phase differences in the model species, and we independently validate this model by showing that the in silico model reproduces much of the behavior that is observed in vitro under genetic knockout conditions. Because our model produces valid phase responses, it can be used in a model predictive control algorithm to determine inputs to shift phase. Our model allows us to consider multi-input control through small molecules that act on both feedback loops, and we find that changes to the parameters of the negative feedback loop are much stronger inputs for shifting phase. The strongest inputs predicted by this model provide targets for new experimental small molecules and suggest that the function of the positive feedback loop is to stabilize the oscillations while linking the circadian system to other clock-controlled processes.

scholarly journals Photic Entrainment of the Circadian System

2022 ◽  
Vol 23 (2) ◽  
pp. 729
Author(s):  
Anna Ashton ◽  
Russell G. Foster ◽  
Aarti Jagannath
Keyword(s):  
Circadian Clock ◽  
Molecular Basis ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
External World ◽  
Circadian System ◽  
Suprachiasmatic Nuclei ◽  
Photic Entrainment ◽  
External Time ◽  
Daily Changes

Circadian rhythms are essential for the survival of all organisms, enabling them to predict daily changes in the environment and time their behaviour appropriately. The molecular basis of such rhythms is the circadian clock, a self-sustaining molecular oscillator comprising a transcriptional–translational feedback loop. This must be continually readjusted to remain in alignment with the external world through a process termed entrainment, in which the phase of the master circadian clock in the suprachiasmatic nuclei (SCN) is adjusted in response to external time cues. In mammals, the primary time cue, or “zeitgeber”, is light, which inputs directly to the SCN where it is integrated with additional non-photic zeitgebers. The molecular mechanisms underlying photic entrainment are complex, comprising a number of regulatory factors. This review will outline the photoreception pathways mediating photic entrainment, and our current understanding of the molecular pathways that drive it in the SCN.

scholarly journals Temporal Regulation of Cytokines by the Circadian Clock

2014 ◽  
Vol 2014 ◽  
pp. 1-4 ◽  
Author(s):  
Atsuhito Nakao
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Circadian Clock ◽  
Molecular Mechanisms ◽  
Host Immune System ◽  
Temporal Regulation ◽  
Cytokine Induction ◽  
Clock Proteins ◽  
New Strategies

Several parameters of the immune system exhibit oscillations with a period of approximately 24 hours that refers to “circadian rhythms.” Such daily variations in host immune system status might evolve to maximize immune reactions at times when encounters with pathogens are most likely to occur. However, the mechanisms behind circadian immunity have not been fully understood. Recent studies reveal that the internal time keeping system “circadian clock” plays a key role in driving the daily rhythms evident in the immune system. Importantly, several studies unveil molecular mechanisms of how certain clock proteins (e.g., BMAL1 and CLOCK) temporally regulate expression of cytokines. Since cytokines are crucial mediators for shaping immune responses, this review mainly summarizes the new knowledge that highlights an emerging role of the circadian clock as a novel regulator of cytokines. A greater understanding of circadian regulation of cytokines will be important to exploit new strategies to protect host against infection by efficient cytokine induction or to treat autoimmunity and allergy by ameliorating excessive activity of cytokines.

scholarly journals SDC mediates DNA methylation-controlled clock pace by interacting with ZTL in Arabidopsis

2021 ◽  
Vol 49 (7) ◽  
pp. 3764-3780
Author(s):  
Wenwen Tian ◽  
Ruyi Wang ◽  
Cunpei Bo ◽  
Yingjun Yu ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Circadian Clock ◽  
Molecular Mechanisms ◽  
Dna Methyltransferases ◽  
Feedback Loops ◽  
Circadian Clocks ◽  
Fine Tuning ◽  
Dna Hypomethylation ◽  
Proteolytic Cascade ◽  
Molecular Bases

Abstract Molecular bases of eukaryotic circadian clocks mainly rely on transcriptional-translational feedback loops (TTFLs), while epigenetic codes also play critical roles in fine-tuning circadian rhythms. However, unlike histone modification codes that play extensive and well-known roles in the regulation of circadian clocks, whether DNA methylation (5mC) can affect the circadian clock, and the associated underlying molecular mechanisms, remains largely unexplored in many organisms. Here we demonstrate that global genome DNA hypomethylation can significantly lengthen the circadian period of Arabidopsis. Transcriptomic and genetic evidence demonstrate that SUPPRESSOR OF drm1 drm2 cmt3 (SDC), encoding an F-box containing protein, is required for the DNA hypomethylation-tuned circadian clock. Moreover, SDC can physically interact with another F-box containing protein ZEITLUPE (ZTL) to diminish its accumulation. Genetic analysis further revealed that ZTL and its substrate TIMING OF CAB EXPRESSION 1 (TOC1) likely act downstream of DNA methyltransferases to control circadian rhythm. Together, our findings support the notion that DNA methylation is important to maintain proper circadian pace in Arabidopsis, and further established that SDC links DNA hypomethylation with a proteolytic cascade to assist in tuning the circadian clock.

scholarly journals HIFα regulates developmental myelination independent of autocrine Wnt signaling

2020 ◽  
Author(s):  
Sheng Zhang ◽  
Yan Wang ◽  
Jie Xu ◽  
Wenbin Deng ◽  
Fuzheng Guo
Keyword(s):  
Wnt Signaling ◽  
Neural Development ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Cellular Level ◽  
Oligodendrocyte Progenitor Cells ◽  
A Minor ◽  
Canonical Wnt ◽  
Cns Myelination

AbstractThe developing CNS is exposed to physiological hypoxia, under which hypoxia inducible factor alpha (HIFα) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanisms of HIFα in developmental myelination remain incompletely understood. Previous concept proposes that HIFα regulates CNS developmental myelination by activating the autocrine Wnt/β-catenin signaling in oligodendrocyte progenitor cells (OPCs). Here, by analyzing a battery of genetic mice of both sexes, we presented in vivo evidences supporting an alternative understanding of oligodendroglial HIFα-regulated developmental myelination. At the cellular level, we found that HIFα was required for developmental myelination by transiently controlling upstream OPC differentiation but not downstream oligodendrocyte maturation and that HIFα dysregulation in OPCs but not oligodendrocytes disturbed normal developmental myelination. We demonstrated that HIFα played a minor, if any, role in regulating canonical Wnt signaling in the oligodendroglial lineage or in the CNS. At the molecular level, blocking autocrine Wnt signaling did not affect HIFα-regulated OPC differentiation and myelination. We further identified HIFα-Sox9 regulatory axis as an underlying molecular mechanism in HIFα-regulated OPC differentiation. Our findings support a concept shift in our mechanistic understanding of HIFα-regulated CNS myelination from the previous Wnt-dependent view to a Wnt-independent one and unveil a previously unappreciated HIFα-Sox9 pathway in regulating OPC differentiation.

scholarly journals Nonlinear phenomena in models of the circadian clock

2020 ◽  
Vol 17 (170) ◽  
pp. 20200556
Author(s):  
Inge van Soest ◽  
Marta del Olmo ◽  
Christoph Schmal ◽  
Hanspeter Herzel
Keyword(s):  
Circadian Clock ◽  
Molecular Mechanisms ◽  
Clock Genes ◽  
Period Doubling ◽  
Tissue Level ◽  
Cellular Level ◽  
Nonlinear Phenomena ◽  
Degradation Rates ◽  
Emergence Of Chaos

The mammalian circadian clock is well-known to be important for our sleep–wake cycles, as well as other daily rhythms such as temperature regulation, hormone release or feeding–fasting cycles. Under normal conditions, these daily cyclic events follow 24 h limit cycle oscillations, but under some circumstances, more complex nonlinear phenomena, such as the emergence of chaos, or the splitting of physiological dynamics into oscillations with two different periods, can be observed. These nonlinear events have been described at the organismic and tissue level, but whether they occur at the cellular level is still unknown. Our results show that period-doubling, chaos and splitting appear in different models of the mammalian circadian clock with interlocked feedback loops and in the absence of external forcing. We find that changes in the degradation of clock genes and proteins greatly alter the dynamics of the system and can induce complex nonlinear events. Our findings highlight the role of degradation rates in determining the oscillatory behaviour of clock components, and can contribute to the understanding of molecular mechanisms of circadian dysregulation.

scholarly journals Cellular and Molecular Mechanisms of Functional Hierarchy of Pacemaker Clusters in the Sinoatrial Node: New Insights into Sick Sinus Syndrome

2021 ◽  
Vol 8 (4) ◽  
pp. 43
Author(s):  
Di Lang ◽  
Alexey V. Glukhov
Keyword(s):  
Molecular Mechanisms ◽  
Sinoatrial Node ◽  
Sick Sinus Syndrome ◽  
Ryanodine Receptors ◽  
Heart Rhythm ◽  
Mechanical Stretch ◽  
Cellular Level ◽  
The Body ◽  
P Wave ◽  
Molecular Evidence

The sinoatrial node (SAN), the primary pacemaker of the heart, consists of a heterogeneous population of specialized cardiac myocytes that can spontaneously produce action potentials, generating the rhythm of the heart and coordinating heart contractions. Spontaneous beating can be observed from very early embryonic stage and under a series of genetic programing, the complex heterogeneous SAN cells are formed with specific biomarker proteins and generate robust automaticity. The SAN is capable to adjust its pacemaking rate in response to environmental and autonomic changes to regulate the heart’s performance and maintain physiological needs of the body. Importantly, the origin of the action potential in the SAN is not static, but rather dynamically changes according to the prevailing conditions. Changes in the heart rate are associated with a shift of the leading pacemaker location within the SAN and accompanied by alterations in P wave morphology and PQ interval on ECG. Pacemaker shift occurs in response to different interventions: neurohormonal modulation, cardiac glycosides, pharmacological agents, mechanical stretch, a change in temperature, and a change in extracellular electrolyte concentrations. It was linked with the presence of distinct anatomically and functionally defined intranodal pacemaker clusters that are responsible for the generation of the heart rhythm at different rates. Recent studies indicate that on the cellular level, different pacemaker clusters rely on a complex interplay between the calcium (referred to local subsarcolemmal Ca2+ releases generated by the sarcoplasmic reticulum via ryanodine receptors) and voltage (referred to sarcolemmal electrogenic proteins) components of so-called “coupled clock pacemaker system” that is used to describe a complex mechanism of SAN pacemaking. In this review, we examine the structural, functional, and molecular evidence for hierarchical pacemaker clustering within the SAN. We also demonstrate the unique molecular signatures of intranodal pacemaker clusters, highlighting their importance for physiological rhythm regulation as well as their role in the development of SAN dysfunction, also known as sick sinus syndrome.

Sign in / Sign up

Export Citation Format

Share Document