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Uhrenkontrollierte Gene: Am Ende entscheidet der lange Arm der Uhr
Abstract
Zu Beginn der 2000er-Jahre hielt das Feld der omics-Forschung Einzug in die Chronobiologie. Hier haben sich besonders die Arbeitsgruppen um John Hogenesch und Steve Kay einen Namen gemacht. Microarray-Studien zeigten, dass tausende von Genen tagesrhythmisch – und dabei hoch gewebsspezifisch – reguliert sind. Die circadiane Uhr steuert diese über spezielle regulatorische Elemente in Kombination mit gewebsspezifischen sog. Pionier-Faktoren. Der vergleichsweise simple Schrittmacher überträgt so seinen 24h-Takt auf den Gesamtorganismus und treibt damit ein weit umfangreicheres, umfassenderes Räderwerk der Zeit. Kaum ein biologischer Prozess unseres Körpers ist nicht zumindest in einem gewissen Maße circadian reguliert. Diese Breitenwirkung führt unausweichlich in das Gebiet der Medizin.
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Every mammalian tissue exhibits daily rhythms in gene expression to control the activation of tissue-specific processes at the most appropriate time of the day. Much of this rhythmic expression is thought to be driven cell autonomously by molecular circadian clocks present throughout the body. By manipulating the daily rhythm of food intake in the mouse, we here show that more than 70% of the cycling mouse liver transcriptome loses rhythmicity under arrhythmic feeding. Remarkably, core clock genes are not among the 70% of genes losing rhythmic expression, and their expression continues to exhibit normal oscillations in arrhythmically fed mice. Manipulation of rhythmic food intake also alters the timing of key signaling and metabolic pathways without altering the hepatic clock oscillations. Our findings thus demonstrate that systemic signals driven by rhythmic food intake significantly contribute to driving rhythms in liver gene expression and metabolic functions independently of the cell-autonomous hepatic clock.
The mammalian transcription factors CLOCK and BMAL1 are essential components of the molecular clock that coordinate behavior
and metabolism with the solar cycle. Genetic or environmental perturbation of circadian cycles contributes to metabolic disorders
including type 2 diabetes. To study the impact of the cell-autonomous clock on pancreatic β cell function, we examined pancreatic
islets from mice with either intact or disrupted BMAL1 expression both throughout life and limited to adulthood. We found
pronounced oscillation of insulin secretion that was synchronized with the expression of genes encoding secretory machinery
and signaling factors that regulate insulin release. CLOCK/BMAL1 colocalized with the pancreatic transcription factor PDX1
within active enhancers distinct from those controlling rhythmic metabolic gene networks in liver. We also found that β cell
clock ablation in adult mice caused severe glucose intolerance. Thus, cell type–specific enhancers underlie the circadian
control of peripheral metabolism throughout life and may help to explain its dysregulation in diabetes.
Significance
We generated high-resolution multiorgan expression data showing that nearly half of all genes in the mouse genome oscillate with circadian rhythm somewhere in the body. Such widespread transcriptional oscillations have not been previously reported in mammals. Applying pathway analysis, we observed new clock-mediated spatiotemporal relationships. Moreover, we found a majority of best-selling drugs in the United States target circadian gene products. Many of these drugs have relatively short half-lives, and our data predict which may benefit from timed dosing.
Like most organisms, plants have endogenous biological clocks that coordinate internal events with the external environment.
We used high-density oligonucleotide microarrays to examine gene expression in Arabidopsis and found that 6% of the more than 8000 genes on the array exhibited circadian changes in steady-state messenger RNA levels.
Clusters of circadian-regulated genes were found in pathways involved in plant responses to light and other key metabolic
pathways. Computational analysis of cycling genes allowed the identification of a highly conserved promoter motif that we
found to be required for circadian control of gene expression. Our study presents a comprehensive view of the temporal compartmentalization
of physiological pathways by the circadian clock in a eukaryote.
Many mammalian peripheral tissues have circadian clocks; endogenous oscillators that generate transcriptional rhythms thought to be important for the daily timing of physiological processes. 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 (> or = 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.
In mammals, circadian control of physiology and behavior is driven by a master pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus. We have used gene expression profiling to identify cycling transcripts in the SCN and in the liver. Our analysis revealed approximately 650 cycling transcripts and showed that the majority of these were specific to either the SCN or the liver. Genetic and genomic analysis suggests that a relatively small number of output genes are directly regulated by core oscillator components. Major processes regulated by the SCN and liver were found to be under circadian regulation. Importantly, rate-limiting steps in these various pathways were key sites of circadian control, highlighting the fundamental role that circadian clocks play in cellular and organismal physiology.
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.
Sleep-wake cycles at mouse synapses
Analysis of the transcriptome, proteome, and phosphoproteome at synapses in the mouse brain during daily sleep-wake cycles reveals large dynamic changes (see the Perspective by Cirelli and Tononi). Noya et al. found that almost 70% of transcripts showed changes in abundance during daily circadian cycles. Transcripts and proteins associated with synaptic signaling accumulated before the active phase (dusk for these nocturnal animals), whereas messenger RNAs and protein associated with metabolism and translation accumulated before the resting phase. Brüning et al. found that half of the 2000 synaptic phosphoproteins quantified showed changes with daily activity-rest cycles. Sleep deprivation abolished nearly all (98%) of these phosphorylation cycles at synapses.
Science , this issue p. eaav2642 , p. eaav3617 ; see also p. 189
Forkhead box (Fox) transcription factors are evolutionarily conserved in organisms ranging from yeast to humans. They regulate diverse biological processes both during development and throughout adult life. Mutations in many Fox genes are associated with human disease and, as such, various animal models have been generated to study the function of these transcription factors in mechanistic detail. In many cases, the absence of even a single Fox transcription factor is lethal. In this Primer, we provide an overview of the Fox family, highlighting several key Fox transcription factor families that are important for mammalian development.
A diurnal rhythm of eating-fasting promotes health, but the eating pattern of humans is rarely assessed. Using a mobile app, we monitored ingestion events in healthy adults with no shift-work for several days. Most subjects ate frequently and erratically throughout wakeful hours, and overnight fasting duration paralleled time in bed. There was a bias toward eating late, with an estimated <25% of calories being consumed before noon and >35% after 6 p.m. "Metabolic jetlag" resulting from weekday/weekend variation in eating pattern akin to travel across time zones was prevalent. The daily intake duration (95% interval) exceeded 14.75 hr for half of the cohort. When overweight individuals with >14 hr eating duration ate for only 10-11 hr daily for 16 weeks assisted by a data visualization (raster plot of dietary intake pattern, "feedogram") that we developed, they reduced body weight, reported being energetic, and improved sleep. Benefits persisted for a year.
Cell physiology is regulated by a 24-hour clock, consisting of interconnected molecular loops, involving at least nine genes. The cellular clock is coordinated by the suprachiasmatic nucleus, a hypothalamic pacemaker which also helps the organism to adjust to environmental cycles. This circadian organisation brings about predictable changes in the body's tolerance and tumour responsiveness to anticancer agents, and possibly also for cancer promotion or growth. The clinical relevance of the chronotherapy principle, ie treatment regimens based upon circadian rhythms, has been demonstrated in randomised, multicentre trials. Chronotherapeutic schedules have been used to document the safety and activity of oxaliplatin against metastatic colorectal cancer and have formed the basis for a new approach to the medicosurgical management of this disease, which achieved unprecedented long-term survival. The chronotherapy concept offers further promise for improving current cancer-treatment options, as well as for optimising the development of new anticancer or supportive agents.
DNA microarrays have found widespread use as a flexible tool to investigate bacterial metabolism. Their main advantage is the comprehensive data they produce on the transcriptional response of the whole genome to an environmental or genetic stimulus. This allows the microbiologist to monitor metabolism and to define stimulons and regulons. Other fields of application are the identification of microorganisms or the comparison of genomes. The importance of this technology increases with the number of sequenced genomes and the falling prices for equipment and oligonucleotides. Knowledge of DNA microarrays is of rising relevance for many areas in microbiological research. Much literature has been published on various specific aspects of this technique that can be daunting to the casual user and beginner. This article offers a comprehensive outline of microarray technology for transcription analysis in microbiology. It shortly discusses the types of DNA microarrays available, the printing of custom arrays, common labeling strategies for targets, hybridization, scanning, normalization, and clustering of expression data.