Communicating clocks form circadian homeostasis

BACKGROUND

Life forms ranging from bacteria to humans are programmed by circadian clocks – mechanisms that place a ~ 24 hour rhythmic impact 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 a molecular machinery that oscillates autonomously. With a genetic basis for the clock, complex organisms can consolidate the timing in specialized cells and anatomical regions, or they can spread this task to all cells through ubiquitous expression. Studies in 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. In the propulsion of daily cycles of homeostatic processes, the mammalian system functions as coupled cell and tissue clocks that extend across the brain and peripheral organs. Recent advances have shed light on how constituent clocks communicate to generate complex rhythms at every level of physiology.

ADVANTAGES

In the brain, the 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 in antiphase oscillates into neurons and is in itself sufficient to drive rhythms in mice. This performance depends on the neurotransmitter interaction that connects the two cell types. In the forebrain, the sleep-wake cycle controls the daily accumulation and phosphorylation of synaptic proteins, which adds an additional layer of post-transcriptional circadian regulation to neuronal function.

Studies in peripheral organs have shown how cellular clocks bring about temporary coherence. Pancreatic islets determine the release of insulin, glucagon and somatostatin to determine the phase relationships of the α, β and δ cells and thus establish a basal layer of synchrony. Single-core sequencing of isolated liver cell populations shows how clock perturbation in hepatocytes affects the molecular rhythms of neighboring endothelial and immune cells, suggesting that circadian programming may be transferred from one cell type to another, perhaps to temporarily integrate different functional niches. Peripheral clocks also work systematically on distal clocks — a growing array of tissues secretes bona fide synchronization factors into the circulation, including skeletal muscle, intestinal, liver, and adipose tissue.

In addition to tissue-specific loss of function experiments, tissue-specific reconstitution of the clock in otherwise clockless mice shows 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 results from the interaction 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 hormone and metabolite fluctuations generated by the clock in other tissues.

OUTLOOK

In modern society, we make conscious decisions, often out of necessity, to dominate our clock programming. As a result, our rhythms can be dissonant with the environment and if not corrected, it can have detrimental effects on health. Circadian maladaptation, in which eating and sleeping patterns resist their natural tendency against the light-dark cycle, disrupt homeostasis and lead to internal imbalance – a feature of diseases ranging from metabolic syndrome to cancer. In contrast, proper alignment and internal synchronization have been shown to combat tissue function and promote well-being. Our innate circadian biology therefore presents challenges and opportunities. Since the disruption of the clock is also the result of disease, it is a task for researchers to identify the range of mechanisms by which clock-to-clock communication is achieved, and then to understand why the mechanisms fail. Restoring timing and coordination between times can be a promising path for therapeutic interventions.