Specific Drosophila circadian neurons — whose activity cycles over the 24-hour period — are known to promote morning and evening peak locomotor activity, but their involvement in sleep control has been unclear. Now, Michael Rosbash and colleagues identify a subset of dorsal clock neurons, called DN1s, as sleep-promoting cells, participating in a feedback loop with pacemaker neurons to drive both midday siesta and night-time sleep. They further observe that DN1 neuronal activity differs between males and females and responds to temperature, consistent with a role for these factors in daytime sleep. Also in this issue of Nature, Gero Miesenböck and colleagues report that sleep-promoting dopaminergic neurons that innervate the Drosophila fan-shaped body switch between electrical activity and silence as a function of sleep requirement.
2017 Nobel Prize in Physiology or Medicine
The 2017 Nobel Prize in Physiology or Medicine was awarded to Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their elucidation of the molecular mechanisms controlling circadian rhythm. Their pioneering work in Drosophila uncovered the internal oscillators, or clocks, that synchronise cellular metabolism and organismal behaviour to the light/dark cycle to generate biological rhythms with 24 hour periodicity.
From the winners
Most animal cells, even in tissue cultures, can develop the molecular oscillations underlying circadian rhythms. To harness this property into the complex time-related behavioural patterns seen in whole organisms requires the intervention of a series of individual brain oscillators. Drosophila is proving to be a good model in which to study this system. The flies manifest characteristic morning and evening locomotor activity, each controlled by a different group of adult brain clock neurons. Now, by generating transgenic animals with different circadian periods in these morning and evening cells, the brain clock cells are shown to be organized into two separate neuronal circuits. One circuit includes the morning and evening cells and drives circadian locomotor activity. The timing of the evening cells is determined by the morning cells as a result of a daily resetting signal from the morning to the evening cells, which then run at their genetically programmed pace between signals.
News and Comments
Plants contain several tissue-specific decentralized but communicating ‘clocks’. These control developmental outputs in response to environmental change: the vasculature clock for photoperiodic control of flowering, and the epidermis clock for temperature-dependent elongation.
Master circadian clocks in discrete neurons trigger profound daily changes in brain states, such as sleep and wake states. A study now finds a circuit through which these pacemakers act to control daily behavioral rhythms in Drosophila.
Many aspects of sleep, including the how and why, are still mysterious, especially its relationship to learning and memory. A new study suggests that sleep may serve to reset synaptic potentiation, linking it to homeostatic plasticity.
The Per2 gene is a core component of the circadian clock in mammals. It now seems that the mouse Per2 gene is also involved in suppressing tumours, through other genes that affect cell proliferation and death.
Circadian regulation of epigenetic chromatin marks drives daily transcriptional oscillation of thousands of genes and is intimately linked to cellular metabolism and bioenergetics. New work links circadian fluctuations in the activity of the SIRT1 deacetylase, a sensor of the cellular energy state, to histone-methylation changes and the circadian expression of clock-controlled genes.
The robustness of the circadian clock deteriorates with aging. Two new studies show that aging reprograms the circadian transcriptome in a cell-type-dependent manner and that such rewiring can be reversed by caloric restriction.
Genetic and biochemical assays reveal that carbon monoxide produced by heme catabolism influences circadian rhythm in mammals by altering the activity of transcription factor CLOCK–BMAL1 at clock-gene targets.
The effect of the liver clock is modified by food entrainment via Bmal1/Clock core machinery. Here the authors show that insulin promotes postprandial Akt-dependent phosphorylation of Bmal1, resulting in association with 14-3-3 and Bmal1 shuttling out of the nucleus, thereby disrupting Bmal1 transcriptional effects on the clock.
This study finds that mice's biological clocks are permanently influenced by the seasonal photoperiod at and after birth. In mice raised under summer-like light periods, rhythmic gene expression in the suprachiasmatic nucleus was tightly correlated with lights-off under both summer- and winter-like cycles. In 'winter-born' mice, these rhythms were tightly correlated only under winter-like light cycles.
GWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person
Circadian rhythms and related behaviours vary across individuals. Here, a large genome-wide association study reveals common single nucleotide variants influencing whether an individual reports as being a ‘morning person’ by identifying 15 significant loci, including 7 near known circadian genes.
Trypanosoma brucei, which is responsible for human sleeping sickness, has an intrinsic circadian clock that regulates metabolism and influences drug sensitivity.
New data show that Clock–Bmal1, the central transcriptional activator that drives expression of circadian target genes, also recruits the Ddb1–Cullin-4 ubiquitin ligase to clock promoters to enhance the subsequent binding of the feedback repressors that generate the circadian periodicity of gene expression.
Circadian- and UPR-dependent control of CPEB4 mediates a translational response to counteract hepatic steatosis under ER stress
Maillo et al. show that in hepatocytes ER stress upregulates CPEB4 through the UPR and circadian clock, leading to CPEB4-mediated translation for mitochondrial and ER homeostasis. CPEB4 loss leads to ageing- and high fat diet-induced liver steatosis.
The evening complex coordinates plant growth and environmental signalling with the circadian clock. Here, a comprehensive dataset of direct transcriptional targets of the evening complex uncovers a high-quality global regulatory network.
Genetic deletion of HDAC3, a circadian epigenome regulator, specifically in skeletal muscle alters amino acid metabolism, leading to increased muscle endurance but at the cost of whole-body insulin resistance.
The cryptochrome/photolyase family of photoreceptors mediates cellular responses to ultraviolet and blue light exposure in all kingdoms of life: cryptochromes transduce signals important for growth, development, magnetosensitivity and circadian clocks, and photolyases repair photolesions in DNA. Zoltowski et al. have now solved the X-ray crystal structure of full-length cryptochrome from Drosophila. They find that a C-terminal helix docks in a groove that is known to bind DNA substrates in photolyases, and a conserved tryptophan protrudes into the catalytic centre of the cryptochrome, mimicking how DNA-repair photolyases recognize lesions in DNA.
Accumulating evidence suggests that microRNAs play a role in circadian regulation. Here the authors show that in theDrosophila brain, mir-92a suppresses the excitability of PDF neurons—key circadian pacemaker cells in Drosophila—via inhibiting the translation of its target sirt2.
This study characterizes a subset of clock neurons known as large lateral-ventral neurons and their dopaminergic/octopaminergic input circuitry in balancing light-mediated wakefulness in Drosophila.
CLOCK (CLK) is essential for the development and maintenance of circadian rhythms in Drosophila. Here, the authors show that Clk mRNA is regulated by miRNA bantam, and deletion of bantambinding site leads to stochastic CLK-driven transcription and development of the circadian neurons.
This study uses a new method of profiling cell type–specific gene expression to identify genes expressed in fruitfly clock neurons. Such profiling yields two novel circadian genes, in separate sets of clock neurons and with differing circadian functions.
The circadian clock plays a central part in the regulation of liver function. In this Review, Tahara and Shibata discuss the mechanisms by which the circadian clock controls hepatic metabolism and the processing of xenobiotics, and how clock dysfunction can influence liver disease.
This perspective discusses the role of epigenetic mechanisms in regulating circadian rhythms, and emphasizes that the role of peripheral machinery is key for a fuller understanding of this regulation.
Clock proteins are controlled by multiple post-translational modifications during the circadian cycle. In this Review, the authors examine how post-translational modifications influence the stability, interactions and activity of mammalian clock proteins and how they contribute to proper clock function or are altered in circadian disorders.
What is the driving force behind periodic biological oscillations such as the circadian, hibernation and sleep–wake cycles? Temporal compartmentalization of metabolism has been shown in budding yeast, and might form the underlying basis for many of the rhythmic phenomena in biology.
Circadian rhythms are well established as having an important role in human biology. In this Review, circadian biology is presented in reference to the regulation of rheumatoid arthritis and the potential for chronotherapeutic intervention.
Evidence indicates that the disruption of the circadian clock might be directly linked to cancer. As described here, alterations in clock function could lead to aberrant cellular proliferation, DNA damage responses and altered metabolism.
Disruption of circadian rhythms in neurodegenerative disorders not only contributes to morbidity and poor quality of life, but could also be involved in driving the disease process itself. Restoration of circadian rhythmicity via behavioural or pharmacological interventions might, therefore, slow down disease progression. In this Review, Videnovic and colleagues provide an overview of the circadian system, and summarize current understanding of the dysfunction of circadian rhythms in Alzheimer disease, Parkinson disease and Huntington disease.
Adequate circadian oscillation of endocrine factors is essential in the maintenance of metabolic homeostasis. The authors of this Review explain the influence of extrinsic and intrinsic factors on endocrine circadian rhythms and how dysregulation of these rhythms can lead to disease in animals and humans. They also discuss therapeutic strategies to restore circadian rhythmicity and improve metabolism.