Communicating clocks shape circadian homeostasis

BACKGROUND

Life forms ranging from bacteria to humans are programmed by circadian clocks – mechanisms that impose a ~ 24 hour rhythm on biology in harmony with geophysical time. Our understanding of circadian rhythms has been transformed by the identification of clock genes and the discovery that these genes encode molecular machinery that oscillates autonomously. With a genetic basis for the clock, complex organisms can consolidate timing into specialized cells and anatomical regions, or they can disperse this task to all cells through ubiquitous expression. Studies on plants, flies and mice have revealed a wide range of organizations of circadian clock systems across species, all of which depend on the passage of circadian information between cells. By boosting the daily cycles of homeostatic processes, the mammalian system functions as clocks coupled with cells and tissues that encompass the brain and peripheral organs. Recent advances have shed light on how constituent clocks communicate to generate intricate rhythms at all levels of physiology.

ADVANCES

In the brain, the activity of the central clock (also known as a pacemaker) in the suprachiasmatic nucleus is driven by neurons and astrocytes. Real-time luciferase and calcium imaging techniques have revealed that astrocytes harbor their own molecular clock, which oscillates in antiphase for neurons and is markedly sufficient on its own to boost rhythms in mice. This feat depends on the interaction of the neurotransmitter that couples the two types of cells. In the forebrain, the sleep-wake cycle controls the daily accumulation and phosphorylation of synaptic proteins, adding an additional layer of post-transcriptional circadian regulation to neuronal function.

Studies on peripheral organs have shown how cell clocks achieve temporal coherence. The pancreatic islets time the release of insulin, glucagon and somatostatin to determine the phase relationships of resident cells α, β and δ, thus establishing a basal layer of synchrony. Single-core sequencing of isolated liver cell populations shows how the disruption of the clock in hepatocytes influences the molecular rhythms of neighboring endothelial and immune cells, suggesting that circadian programming can be passed from one cell type to another, perhaps to temporarily integrate different functional niches. Peripheral clocks also act systemically on distal clocks – a growing list of tissues secrete genuine synchronization factors into the circulation, including skeletal muscle, intestines, liver and adipose tissues.

Complementing the tissue-specific function loss experiments, the specific reconstitution of clock tissue in rats without a clock demonstrates that peripheral clocks are only sufficient to drive a small fraction of local rhythms and therefore depend heavily on circadian input signals. Extrinsic transcriptional control derives from the cooperation of the molecular clock with lineage-specific transcription factors in gene promoters and enhancers. Through interactions with clock proteins, nuclear receptors regulate specific sets of genes in response to fluctuations in hormones and metabolites generated by the clock in other tissues.

PANORAMA

In modern society, we make conscious decisions, often out of necessity, to replace our clock schedule. As a result, our rhythms can be dissonant with the environment and, if not corrected, can cause adverse health effects. Circadian misalignment, in which eating and sleeping patterns are opposed to the natural inclination of the light-dark cycle, disturbs homeostasis and leads to internal imbalance – a characteristic of diseases ranging from the metabolic syndrome to cancer. In contrast, proper alignment and internal synchrony have been shown to combat tissue dysfunction and promote well-being. Thus, our innate circadian biology presents challenges and opportunities. Since the interruption of the clock is also a consequence of the disease, a task for researchers is to identify the set of mechanisms through which clock-to-clock communication is achieved and then to understand why these mechanisms fail. Restoring time and coordination between tissues can serve as a promising path for therapeutic interventions.