Review

Circadian time signatures of fitness and disease

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Science  25 Nov 2016:
Vol. 354, Issue 6315, pp. 994-999
DOI: 10.1126/science.aah4965

Figures

  • Fig. 1 Geophysical time drives circadian maintenance of homeostasis.

    The molecular clock is composed of an autoregulatory negative transcription feedback loop that synchronizes physiology and behavior in anticipation of the light-dark cycle. The illustration depicts variation in physiology for diurnal species (active in light); however, circadian cycles also govern sleep/wake and physiologic processes in nocturnal species (active in the dark), with an inverted phase. Exposure to sunlight induces DNA damage each day while also providing energy for oxygenic photosynthesis, processes that may explain the evolution of circadian clocks across four kingdoms of life. Clocks partition oxygenic and reductive metabolic cycles each day and separate these in coordination with the sleep/wake cycle. Although many physiologic processes maintain constancy of the internal milieu, including glucose metabolism, response to perturbation is tuned to circadian time.

  • Fig. 2 Molecular regulation of cellular circadian processes.

    A unifying model of the circadian system involves a defined set of core clock genes that are essential for generation of ~24-hour oscillation in genome-wide transcription. The heterodimeric basic helix-loop-helix TFs CLOCK/BMAL1 and the CLOCK paralog NPAS2 compose the forward limb of the mammalian clock and bind to genomic enhancer elements to positively control circadian clock output genes as well as two distinct repressive pathways required for the negative feedback inherent in clock function. The repressive pathways involve the heterodimeric basic helix-loop-helix TFs PER/CRY and NRs Rev-erbα/β, which function both competitively and noncompetitively with activating ROR NRs at Rev-erb/ROR-response element (RRE)–containing enhancers that control Bmal1 transcription as well as circadian clock output genes. The clock cycle is regulated through turnover of the repressors after phosophorylation mediated by CK1e/d and executed through ubiquitin-mediated proteasomal degradation involving FBXL3. Posttranscriptional regulation also plays a role in physiologic rhythms, including rhythmic regulation of RNA polyadenylation. Clock factors act through both direct and indirect mechanisms through binding to cell type–specific enhancers far from the transcription start site to regulate a wide array of clock-controlled genes. Both generation of the core clock transcription cycle and its output rhythms engage numerous epigenetic modifiers such as HDACs, methyltransferases, and nucleosome remodeling factors. Clock cycles are also sensitive to environmental signals, including metabolites, DNA damage activation, and signal transduction pathways, all of which feedback to modulate rhythmic transcription but do so differently in distinct tissues in both physiologic and pathologic states. HLF, hepatic leukemia factor; TEF, thyrotroph embryonic factor; DBP, albumin D-box binding protein.

  • Fig. 3 Circadian systems in physiological cross-talk and disease.

    The circadian system is organized hierarchically with master pacemaker neurons in the central nervous system entrained to light each day, in turn conducting a distributed network of local clocks expressed in most peripheral cells and tissues. Within the brain, the clock plays a role not only in maintaining the timing of sleep/wake cycle relative to light but also in many behaviors, including learning, reward, and neurogenesis. Peripheral tissue clocks are entrained to the brain clock, although feeding and temperature are dominant in some physiological settings. Peripheral clocks may also become uncoupled and desynchronized from the central pacemaker during aging, shiftwork, jet travel, overnutrition, obesity, or cancer. Circadian disruption and associated impairment in sleep contributes to the molecular pathogenesis of disorders such as metabolic syndrome, obesity, diabetes, autoimmunity, and cancer.

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