CircaDB: a database of mammalian circadian gene expression profiles
TL;DR: A new database of circadian transcriptional profiles from time course expression experiments from mice and humans, where each transcript’s expression was evaluated by three separate algorithms, JTK_Cycle, Lomb Scargle and DeLichtenberg.
Abstract: CircaDB (http://circadb.org) is a new database of circadian transcriptional profiles from time course expression experiments from mice and humans. Each transcript’s expression was evaluated by three separate algorithms, JTK_Cycle, Lomb Scargle and DeLichtenberg. Users can query the gene annotations using simple and powerful full text search terms, restrict results to specific data sets and provide probability thresholds for each algorithm. Visualizations of the data are intuitive charts that convey profile information more effectively than a table of probabilities. The CircaDB web application is open source and available at http:// github.com/itmat/circadb.
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TL;DR: The results show that the circadian clock generates oscillations in mitochondrial oxidative capacity through rhythmic regulation of NAD+ biosynthesis, and facilitates oxidative rhythms that correspond with the fasting-feeding cycle to maximize energy production during rest.
Abstract: Circadian clocks are self-sustained cellular oscillators that synchronize oxidative and reductive cycles in anticipation of the solar cycle. We found that the clock transcription feedback loop produces cycles of nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, adenosine triphosphate production, and mitochondrial respiration through modulation of mitochondrial protein acetylation to synchronize oxidative metabolic pathways with the 24-hour fasting and feeding cycle. Circadian control of the activity of the NAD(+)-dependent deacetylase sirtuin 3 (SIRT3) generated rhythms in the acetylation and activity of oxidative enzymes and respiration in isolated mitochondria, and NAD(+) supplementation restored protein deacetylation and enhanced oxygen consumption in circadian mutant mice. Thus, circadian control of NAD(+) bioavailability modulates mitochondrial oxidative function and organismal metabolism across the daily cycles of fasting and feeding.
522 citations
Cites background from "CircaDB: a database of mammalian ci..."
...S5A) (20), as well as phosphofructokinase 1 (Pfk1), a rate-limiting glycolytic enzyme (fig....
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TL;DR: The molecular, cellular and circuit mechanisms underlying time-keeping in the SCN are examined, which act as the principal pacemaker for circadian rhythms, which are powerful regulators of physiology and behaviour in mammals.
Abstract: The suprachiasmatic nucleus (SCN) of the hypothalamus is remarkable. Despite numbering only about 10,000 neurons on each side of the third ventricle, the SCN is our principal circadian clock, directing the daily cycles of behaviour and physiology that set the tempo of our lives. When this nucleus is isolated in organotypic culture, its autonomous timing mechanism can persist indefinitely, with precision and robustness. The discovery of the cell-autonomous transcriptional and post-translational feedback loops that drive circadian activity in the SCN provided a powerful exemplar of the genetic specification of complex mammalian behaviours. However, the analysis of circadian time-keeping is moving beyond single cells. Technical and conceptual advances, including intersectional genetics, multidimensional imaging and network theory, are beginning to uncover the circuit-level mechanisms and emergent properties that make the SCN a uniquely precise and robust clock. However, much remains unknown about the SCN, not least the intrinsic properties of SCN neurons, its circuit topology and the neuronal computations that these circuits support. Moreover, the convention that the SCN is a neuronal clock has been overturned by the discovery that astrocytes are an integral part of the timepiece. As a test bed for examining the relationships between genes, cells and circuits in sculpting complex behaviours, the SCN continues to offer powerful lessons and opportunities for contemporary neuroscience.
518 citations
TL;DR: It is shown that mitochondrial dynamics (notably fission and mitophagy) and biogenesis are transcriptional targets of the circadian regulator Bmal1 in mouse liver and exhibit a metabolic rhythm in sync with diurnal bioenergetic demands.
264 citations
Cites methods from "CircaDB: a database of mammalian ci..."
...Based on the Circa database (Pizarro et al., 2013), the majority of the 211 genes in the liver peaked at ZT12 (Figure 5C)....
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Karolinska Institutet1, University of Fribourg2, Northwestern University3, University of Zurich4, University of Queensland5, University of Texas Southwestern Medical Center6, Laboratory of Molecular Biology7, University of Würzburg8, Cincinnati Children's Hospital Medical Center9, French Institute of Health and Medical Research10, University of Manchester11, Max Planck Society12, Leiden University Medical Center13, Howard Hughes Medical Institute14, Rockefeller University15
TL;DR: There is emerging evidence showing that some drugs are more effective at nighttime than daytime, whereas for others it is the opposite, which suggests that the biology of the target cell will determine how an organ will respond to a drug at a specific time of the day, thus modulating pharmacodynamics.
215 citations
TL;DR: The mechanisms that regulate potassium homeostasis are reviewed and the important role that the circadian clock exerts on these processes is described.
Abstract: The plasma potassium level is normally maintained within narrow limits by multiple mechanisms. This article reviews the mechanisms that regulate potassium homeostasis and describes the important role that the circadian clock exerts on these processes.
213 citations
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TL;DR: In this paper, high-density oligonucleotide arrays offer the opportunity to examine patterns of gene expression on a genome scale, and the authors have designed custom arrays that interrogate the expression of the vast majority of proteinencoding human and mouse genes and have used them to profile a panel of 79 human and 61 mouse tissues.
Abstract: The tissue-specific pattern of mRNA expression can indicate important clues about gene function. High-density oligonucleotide arrays offer the opportunity to examine patterns of gene expression on a genome scale. Toward this end, we have designed custom arrays that interrogate the expression of the vast majority of protein-encoding human and mouse genes and have used them to profile a panel of 79 human and 61 mouse tissues. The resulting data set provides the expression patterns for thousands of predicted genes, as well as known and poorly characterized genes, from mice and humans. We have explored this data set for global trends in gene expression, evaluated commonly used lines of evidence in gene prediction methodologies, and investigated patterns indicative of chromosomal organization of transcription. We describe hundreds of regions of correlated transcription and show that some are subject to both tissue and parental allele-specific expression, suggesting a link between spatial expression and imprinting.
3,513 citations
"CircaDB: a database of mammalian ci..." refers methods in this paper
...The Database of Circadian Gene Expression (24), part of the Gene Atlas Project (32), contains a subset of the same data sets in CircaDB, but uses a single circadian expression algorithm....
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TL;DR: Genetic and genomic analysis suggests that a relatively small number of output genes are directly regulated by core oscillator components, and major processes regulated by the SCN and liver were found to be under circadian regulation.
2,227 citations
"CircaDB: a database of mammalian ci..." refers methods in this paper
...The Database of Circadian Gene Expression (24), part of the Gene Atlas Project (32), contains a subset of the same data sets in CircaDB, but uses a single circadian expression algorithm....
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TL;DR: The general mechanisms of the circadian clockwork are reviewed, recent findings that elucidate tissue-specific expression patterns of the clock genes are described and the importance of circadian regulation in peripheral tissues for an organism's overall well-being is addressed.
Abstract: Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus. Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases. Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature. At the level of individual tissues, thousands of genes are brought to unique phases through the actions of a local transcription/translation-based feedback oscillator and systemic cues. In this molecular clock, the proteins CLOCK and BMAL1 cause the transcription of genes which ultimately feedback and inhibit CLOCK and BMAL1 transcriptional activity. Finally, there are also other molecular circadian oscillators which can act independently of the transcription-based clock in all species which have been tested.
1,550 citations
TL;DR: A comparative analysis of circadian gene expression in vivo in mouse liver and heart using oligonucleotide arrays representing 12,488 genes finds that peripheral circadian gene regulation is extensive, that the distributions of circadian phases in the two tissues are markedly different, and that very few genes show circadian regulation in both tissues.
Abstract: Many mammalian peripheral tissues have circadian clocks1,2,3,4; endogenous oscillators that generate transcriptional rhythms thought to be important for the daily timing of physiological processes5,6. The extent of circadian gene regulation in peripheral tissues is unclear, and to what degree circadian regulation in different tissues involves common or specialized pathways is unknown. Here we report a comparative analysis of circadian gene expression in vivo in mouse liver and heart using oligonucleotide arrays representing 12,488 genes. We find that peripheral circadian gene regulation is extensive (≥8–10% of the genes expressed in each tissue), that the distributions of circadian phases in the two tissues are markedly different, and that very few genes show circadian regulation in both tissues. This specificity of circadian regulation cannot be accounted for by tissue-specific gene expression. Despite this divergence, the clock-regulated genes in liver and heart participate in overlapping, extremely diverse processes. A core set of 37 genes with similar circadian regulation in both tissues includes candidates for new clock genes and output genes, and it contains genes responsive to circulating factors with circadian or diurnal rhythms.
1,493 citations
TL;DR: Together, these studies set the scene for applying the knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.
Abstract: Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.
1,392 citations