Communicating clocks shape circadian homeostasis

doi:10.1126/science.abd0951

GSTDTAP > 气候变化

DOI	10.1126/science.abd0951
	Communicating clocks shape circadian homeostasis
	Kevin B. Koronowski; Paolo Sassone-Corsi
	2021-02-12
发表期刊	Science
出版年	2021
英文摘要	Circadian rhythms that affect multiple tissues and organ systems are aligned with the dark-light cycle and other external inputs such as feeding. But how is such time keeping modulated throughout complex systems and anatomical regions? Koronowski and Sassone-Corsi reviewed how central regulators in the brain and peripheral regulators throughout organs can behave cooperatively or independently to modulate circadian rhythms. This systemic view of circadian rhythm modulation is important to understand behavior and disease, because dysregulated clocks are associated with metabolic syndrome and cancer. Science , this issue p. [eabd0951][1] ### BACKGROUND Life-forms ranging from bacteria to humans are programmed by circadian clocks—mechanisms that impose an ~24-hour rhythmicity on biology in harmony with geophysical time. Our understanding of circadian rhythms was transformed by the identification of clock genes and the discovery that these genes encode a molecular machinery that oscillates autonomously. With a genetic basis for the clock, complex organisms can consolidate timekeeping in specialized cells and anatomical regions, or they can disperse this task to all cells through ubiquitous expression. Studies in plants, flies, and mice have revealed a vast array of organizations of circadian clock systems across species, all of which rely on the passage of circadian information between cells. In propelling daily cycles of homeostatic processes, the mammalian system functions as coupled cell and tissue clocks that span both the brain and peripheral organs. Recent advances have shed light on how constituent clocks communicate to generate intricate rhythms at every level of physiology. ### ADVANCES In the brain, activity of the central clock (also known as the pacemaker) in the suprachiasmatic nucleus is driven by both neurons and astrocytes. Real-time luciferase and calcium imaging techniques have revealed that astrocytes harbor their own molecular clock, which oscillates in antiphase to neurons and is markedly sufficient on its own to propel rhythms in mice. This feat hinges on neurotransmitter interplay that couples the two cell types. In the forebrain, the sleep-wake cycle controls the daily accumulation and phosphorylation of synaptic proteins, adding an additional layer of posttranscriptional circadian regulation to neuronal function. Studies in peripheral organs have demonstrated how cellular clocks achieve temporal coherence. Pancreatic islets time the release of insulin, glucagon, and somatostatin to determine the phase relationships of resident α, β, and δ cells, thereby establishing a basal layer of synchrony. Single-nucleus sequencing of isolated liver cell populations shows how clock disruption in hepatocytes influences the molecular rhythms of neighboring endothelial and immune cells, which suggests that circadian programming can be passed from one cell type to another, perhaps to temporally integrate different functional niches. Peripheral clocks also act systemically on distal clocks—a growing list of tissues secrete bona fide synchronizing factors into the circulation, including skeletal muscle, intestine, liver, and adipose tissues. Complementing tissue-specific loss-of-function experiments, tissue-specific reconstitution of the clock in otherwise clockless mice demonstrates that peripheral clocks are only sufficient to drive a small fraction of local rhythms and thus rely heavily on incoming circadian signals. Extrinsic transcriptional control stems from the cooperation of the molecular clock with lineage-specific transcription factors at gene promotors and enhancers. Through interactions with clock proteins, nuclear receptors regulate specific sets of genes in response to hormone and metabolite fluctuations generated by the clock in other tissues. ### OUTLOOK In modern society, we make conscious decisions, often out of necessity, to override our clock programming. As a result, our rhythms can be dissonant with the environment and, if left uncorrected, can cause adverse health effects. Circadian misalignment, wherein eating and sleeping patterns oppose their natural inclination from the light-dark cycle, disrupts homeostasis and leads to internal imbalance—a feature of diseases ranging from metabolic syndrome to cancer. By contrast, proper alignment and internal synchrony have been demonstrated to combat tissue dysfunction and promote well-being. Thus, our innate circadian biology presents both challenges and opportunities. Given that clock disruption is also a consequence of disease, a task at hand for researchers is to identify the suite of mechanisms through which clock-to-clock communication is achieved and then understand why those mechanisms fail. Reestablishing intertissue timing and coordination could serve as a promising avenue for therapeutic interventions. ![Figure][2] Cellular to organismal timekeeping: Communication between clocks. The mammalian circadian clock is a coupled network of cell and tissue clocks. Light and food are predominant cues—pushing and pulling on the phase, enhancing or attenuating the amplitude, and activating or inhibiting functional rhythms. In a tissue-specific manner, clocks receive input signals and convert them into timed functional outputs, many of which, in turn, act as inputs and effectively connect the network. CREDIT: N. CARY/ SCIENCE Circadian clocks temporally coordinate physiology and align it with geophysical time, which enables diverse life-forms to anticipate daily environmental cycles. In complex organisms, clock function originates from the molecular oscillator within each cell and builds upward anatomically into an organism-wide system. Recent advances have transformed our understanding of how clocks are connected to achieve coherence across tissues. Circadian misalignment, often imposed in modern society, disrupts coordination among clocks and has been linked to diseases ranging from metabolic syndrome to cancer. Thus, uncovering the physiological circuits whereby biological clocks achieve coherence will inform on both challenges and opportunities in human health. [1]: /lookup/doi/10.1126/science.abd0951 [2]: pending:yes
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/314087
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Kevin B. Koronowski,Paolo Sassone-Corsi. Communicating clocks shape circadian homeostasis[J]. Science,2021.
APA	Kevin B. Koronowski,&Paolo Sassone-Corsi.(2021).Communicating clocks shape circadian homeostasis.Science.
MLA	Kevin B. Koronowski,et al."Communicating clocks shape circadian homeostasis".Science (2021).