scholarly journals The methyl cycle is a conserved regulator of biological clocks

2019 ◽  
Author(s):  
Jean-Michel Fustin ◽  
Shiqi Ye ◽  
Christin Rakers ◽  
Marijke Versteven ◽  
Samantha J. Cargill ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nucleic Acids ◽  
Circadian Clock ◽  
Metabolic Pathway ◽  
Mammalian Cells ◽  
Feedback Loop ◽  
Biological Clocks ◽  
Methyl Donor ◽  
Methyl Cycle ◽  
And Function

AbstractThe methyl cycle is a universally conserved metabolic pathway operating in prokaryotes and eukaryotes. In this pathway, the amino acid methionine is used to synthesize S-adenosylmethionine, the methyl donor co-substrate in the methylation of nucleic acids, histone and non-histone proteins and many other molecules within the cell. The methylation of nucleic acids and proteins is the foundation of epigenetic and epitranscriptomic regulations of gene expression, but whether the methyl cycle centrally regulates gene expression and function by controlling the availability of methyl moieties is poorly understood.From cyanobacteria to humans, a circadian clock that involves an exquisitely regulated transcription-translation-feedback loop driving oscillations in gene expression and orchestrating physiology and behavior has been described. We reported previously that inhibition of the methyl cycle in mammalian cells caused the lengthening of the period of these oscillations, suggesting the methyl cycle may indeed act as a central regulator of gene expression, at least in mammals. Here, we investigated whether the methyl cycle, given its universal presence among living beings, regulates the circadian clock in species across the phylogenetic tree of life.We reveal a remarkable evolutionary conservation of the link between the methyl cycle and the circadian clock. Moreover, we show that the methyl cycle also regulates the somite segmentation clock, another transcription-translation negative feedback loop-based timing mechanism that orchestrate embryonic development in vertebrates, highlighting the methyl cycle as a master regulator of biological clocks.SIGNIFICANCE STATEMENTHere we reveal that the methyl cycle, a universal metabolic pathway leading to the synthesis of S-adenosylmethionine, the methyl donor co-substrate in virtually all transmethylation reactions within the cell, is a conserved regulator of biological clocks. These discoveries highlight the methyl cycle as a metabolic hub that regulates gene expression via the availability of methyl moieties for the methylation of nucleic acids, proteins and many other molecules with the cell.

scholarly journals Minireview: NAD+, a Circadian Metabolite with an Epigenetic Twist

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Paolo Sassone-Corsi
Keyword(s):  
Circadian Clock ◽  
Nicotinamide Adenine Dinucleotide ◽  
Mammalian Cells ◽  
Feedback Loop ◽  
Large Fraction ◽  
Sirtuin 1 ◽  
Nicotinamide Adenine ◽  
Dynamic Changes ◽  
Metabolic Functions ◽  
Transcriptional Feedback

Abstract A wide variety of endocrine, physiological, and metabolic functions follow daily oscillations. Most of these regulations are controlled at the level of gene expression by the circadian clock and, a remarkably coordinated transcription-translation machinery that exerts its function in virtually all mammalian cells. A large fraction of the genome is under control of the circadian clock, a regulation that is achieved through dynamic changes in chromatin states. Recent findings have demonstrated intimate connections between the circadian clock and epigenetic control. The case of nicotinamide adenine dinucleotide, which modulates the circadian activity of the deacetylase sirtuin 1, constitutes a paradigmatic example of the link between cyclic cellular metabolism and chromatin remodeling. Indeed, the clock transcriptional feedback loop is interlocked with the enzymatic loop of the nicotinamide adenine dinucleotide salvage pathway.

scholarly journals Identification of the Pseudorabies Virus Promoter Required for Latency-Associated Transcript Gene Expression in the Natural Host

2000 ◽  
Vol 74 (14) ◽  
pp. 6333-6338 ◽  
Author(s):  
Ling Jin ◽  
William M. Schnitzlein ◽  
Gail Scherba
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Pseudorabies Virus ◽  
Consensus Sequence ◽  
Neuronal Cells ◽  
Natural Host ◽  
Lytic Infection ◽  
Latently Infected ◽  
And Function

ABSTRACT Expression of the latency-associated transcript (LAT) gene is a hallmark of alphaherpesvirus latency, and yet its control and function remain an enigma. Resolution of this problem will require verification and subsequent elimination or disabling of elements regulating LAT gene transcription so that the influence of the resultant RNA can be evaluated. Toward this end, we generated a novel pseudorabies virus (PrV) recombinant in which a 282-bp region containing the LAP1 (first latency-active promoter) consensus sequence was replaced by a reporter cassette. Despite this substitution, replication of the recombinant was comparable to that of the parental and rescuant viruses both in cultured mammalian cells and in the natural host, swine. Furthermore, production of the LAT gene-associated 2.0- and 8.0-kb RNAs during an in vitro lytic infection of cultured neuronal cells was unaffected. However, the otherwise constitutively produced and processed 8.4-kb LAT was not detected in porcine trigeminal ganglia latently infected with this novel recombinant, although the viral genome was shown to be present. Therefore, LAP1 is apparently the basal promoter for PrV LAT gene expression during viral latency but is not required for such activity during an in vitro lytic infection of neuronal cells. More importantly, the ability of PrV to persist in a latent state in the absence of LAT suggests that other factors are responsible for this event in the natural host.

Oxygen-dependent gene expression in fishes

2005 ◽  
Vol 288 (5) ◽  
pp. R1079-R1090 ◽  
Author(s):  
Mikko Nikinmaa ◽  
Bernard B. Rees
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Hypoxia Inducible Factor ◽  
Transcriptional Response ◽  
Hypoxia Tolerance ◽  
Hypoxic Exposure ◽  
Low Oxygen ◽  
Mammalian Development ◽  
Molecular Responses ◽  
And Function

The role of oxygen in regulating patterns of gene expression in mammalian development, physiology, and pathology has received increasing attention, especially after the discovery of the hypoxia-inducible factor (HIF), a transcription factor that has been likened to a “master switch” in the transcriptional response of mammalian cells and tissues to low oxygen. At present, considerably less is known about the molecular responses of nonmammalian vertebrates and invertebrates to hypoxic exposure. Because many animals live in aquatic habitats that are variable in oxygen tension, it is relevant to study oxygen-dependent gene expression in these animals. The purpose of this review is to discuss hypoxia-induced gene expression in fishes from an evolutionary and ecological context. Recent studies have described homologs of HIF in fish and have begun to evaluate their function. A number of physiological processes are known to be altered by hypoxic exposure of fish, although the evidence linking them to HIF is less well developed. The diversity of fish presents many opportunities to evaluate if inter- and intraspecific variation in HIF structure and function correlate with hypoxia tolerance. Furthermore, as an aquatic group, fish offer the opportunity to examine the interactions between hypoxia and other stressors, including pollutants, common in aquatic environments. It is possible, if not likely, that results obtained by studying the molecular responses of fish to hypoxia will find parallels in the oxygen-dependent responses of mammals, including humans. Moreover, novel responses to hypoxia could be discovered through studies of this diverse and species-rich group.

scholarly journals Methylation deficiency disrupts biological rhythms from bacteria to humans

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Jean-Michel Fustin ◽  
Shiqi Ye ◽  
Christin Rakers ◽  
Kensuke Kaneko ◽  
Kazuki Fukumoto ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Metabolic Pathway ◽  
Mammalian Cells ◽  
Biological Rhythms ◽  
Tree Of Life ◽  
Circadian Clocks ◽  
Methyl Groups ◽  
Cellular Physiology ◽  
Unicellular Algae ◽  
Methyl Cycle

AbstractThe methyl cycle is a universal metabolic pathway providing methyl groups for the methylation of nuclei acids and proteins, regulating all aspects of cellular physiology. We have previously shown that methyl cycle inhibition in mammals strongly affects circadian rhythms. Since the methyl cycle and circadian clocks have evolved early during evolution and operate in organisms across the tree of life, we sought to determine whether the link between the two is also conserved. Here, we show that methyl cycle inhibition affects biological rhythms in species ranging from unicellular algae to humans, separated by more than 1 billion years of evolution. In contrast, the cyanobacterial clock is resistant to methyl cycle inhibition, although we demonstrate that methylations themselves regulate circadian rhythms in this organism. Mammalian cells with a rewired bacteria-like methyl cycle are protected, like cyanobacteria, from methyl cycle inhibition, providing interesting new possibilities for the treatment of methylation deficiencies.

scholarly journals Coordination of robust single cell rhythms in the Arabidopsis circadian clock via spatial waves of gene expression

2017 ◽  
Author(s):  
Peter D. Gould ◽  
Mirela Domijan ◽  
Mark Greenwood ◽  
Isao T. Tokuda ◽  
Hannah Rees ◽  
...  
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Single Cell ◽  
Feedback Loop ◽  
Root Tip ◽  
Single Cell Level ◽  
Cell Coupling ◽  
Cell Level ◽  
Multiple Points ◽  
Spatial Waves

The Arabidopsis circadian clock orchestrates gene regulation across the day/night cycle. Although a multiple feedback loop circuit has been shown to generate the 24h rhythm, it remains unclear how robust the clock is in individual cells, or how clock timing is coordinated across the plant. Here we examine clock activity at the single cell level across Arabidopsis seedlings over several days. Our data reveal robust single cell oscillations, albeit desynchronised. In particular, we observe two waves of clock activity; one going down, and one up the root. We also find evidence of cell-to-cell coupling of the clock, especially in the root tip. A simple model shows that cell-to-cell coupling and our measured period differences between cells can generate the observed waves. Our results reveal the spatial structure of the plant circadian clock and suggest that unlike the centralised mammalian clock, the clock has multiple points of coordination in Arabidopsis.

scholarly journals Ultrasound Imaging of Gene Expression in Mammalian Cells

2019 ◽  
Author(s):  
Arash Farhadi ◽  
Gabrielle H. Ho ◽  
Daniel P. Sawyer ◽  
Raymond W. Bourdeau ◽  
Mikhail G. Shapiro
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Reporter Genes ◽  
Tissue Imaging ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Deep Tissue Imaging ◽  
And Function ◽  
Expression In Mammalian Cells

ABSTRACTThe study of cellular processes occurring inside intact organisms and the development of cell-based diagnostic and therapeutic agents requires methods to visualize cellular functions such as gene expression in deep tissues. Ultrasound is a widely used biomedical technology enabling deep-tissue imaging with high spatial and temporal resolution. However, no genetically encoded molecular reporters are available to connect ultrasound contrast to gene expression in mammalian cells. To address this limitation, we introduce the first mammalian acoustic reporter genes. Starting with an eleven-gene polycistronic gene cluster derived from bacteria, we engineered a eukaryotic genetic program whose introduction into mammalian cells results in the expression of a unique class of intracellular air-filled protein nanostructures called gas vesicles. The scattering of ultrasound by these nanostructures allows mammalian cells to be visualized at volumetric densities below 0.5%, enables the monitoring of dynamic circuit-driven gene expression, and permits high-resolution imaging of gene expression in living animals. These mammalian acoustic reporter genes enable previously impossible approaches to monitoring the location, viability and function of mammalian cellsin vivo.

scholarly journals In vivo bioluminescence for tracking cell fate and function

2011 ◽  
Vol 301 (3) ◽  
pp. H663-H671 ◽  
Author(s):  
Patricia E. de Almeida ◽  
Juliaan R. M. van Rappard ◽  
Joseph C. Wu
Keyword(s):  
Gene Expression ◽  
Cell Survival ◽  
Cell Fate ◽  
Mammalian Cells ◽  
Cardiac Injury ◽  
Therapeutic Interventions ◽  
Luciferase Expression ◽  
Physiological Processes ◽  
And Function

Tracking the fate and function of cells in vivo is paramount for the development of rational therapies for cardiac injury. Bioluminescence imaging (BLI) provides a means for monitoring physiological processes in real time, ranging from cell survival to gene expression to complex molecular processes. In mice and rats, BLI provides unmatched sensitivity because of the absence of endogenous luciferase expression in mammalian cells and the low background luminescence emanating from animals. In the field of stem cell therapy, BLI provides an unprecedented means to monitor the biology of these cells in vivo, giving researchers a greater understanding of their survival, migration, immunogenicity, and potential tumorigenicity in a living animal. In addition to longitudinal monitoring of cell survival, BLI is a useful tool for semiquantitative measurements of gene expression in vivo, allowing a better optimization of drug and gene therapies. Overall, this technology not only enables rapid, reproducible, and quantitative monitoring of physiological processes in vivo but also can measure the influences of therapeutic interventions on the outcome of cardiac injuries.

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