Clock Genes In Tissues Research Articles

Sleep and circadian rhythmicity as entangled processes serving homeostasis.

Sleep is considered essential for the brain and body. A predominant concept is that sleep is regulated by circadian rhythmicity and sleep homeostasis, processes that were posited to be functionally and mechanistically separate. Here we review and re-evaluate this concept and its assumptions using findings from recent human and rodent studies. Alterations in genesthat are central to circadian rhythmicity affect not only sleep timing but also putative markers of sleep homeostasis such as electroencephalogram slow-wave activity (SWA). Perturbations of sleep change the rhythmicity in the expression of core clock genes in tissues outside the central clock. The dynamics of recovery from sleep loss vary across sleep variables: SWA and immediate early genes show an early response, but the recovery ofnon-rapid eye movement and rapid eye movement sleep follows slower time courses. Changes in the expression of many genes in response to sleep perturbations outlast the effects on SWA and time spent asleep. These findings are difficult to reconcile with the notion that circadian- and sleep-wake-driven processes are mutually independent and that the dynamics of sleep homeostasis are reflected in a single variable. Further understanding of how both sleep and circadian rhythmicity contribute to thehomeostasis of essential physiological variables may benefit from the assessment of multiple sleep and molecular variables over longer time scales.

Disrupted circadian clocks and altered tissue mechanics in primary human breast tumours

BackgroundCircadian rhythms maintain tissue homeostasis during the 24-h day-night cycle. Cell-autonomous circadian clocks play fundamental roles in cell division, DNA damage responses and metabolism. Circadian disruptions have been proposed as a contributing factor for cancer initiation and progression, although definitive evidence for altered molecular circadian clocks in cancer is still lacking. In this study, we looked at circadian clocks in breast cancer.MethodsWe isolated primary tumours and normal tissues from the same individuals who had developed breast cancer with no metastases. We assessed circadian clocks within primary cells of the patients by lentiviral expression of circadian reporters, and the levels of clock genes in tissues by qPCR. We histologically examined collagen organisation within the normal and tumour tissue areas, and probed the stiffness of the stroma adjacent to normal and tumour epithelium using atomic force microscopy.ResultsEpithelial ducts were disorganised within the tumour areas. Circadian clocks were altered in cultured tumour cells. Tumour regions were surrounded by stroma with an altered collagen organisation and increased stiffness. Levels of Bmal1 messenger RNA (mRNA) were significantly altered in the tumours in comparison to normal epithelia.ConclusionCircadian rhythms are suppressed in breast tumour epithelia in comparison to the normal epithelia in paired patient samples. This correlates with increased tissue stiffness around the tumour region. We suggest possible involvement of altered circadian clocks in the development and progression of breast cancer.

Scheduled Food Hastens Re-Entrainment More Than Melatonin Does after a 6-h Phase Advance of the Light-Dark Cycle in Rats

Circadian desynchrony occurs when individuals are exposed to abrupt phase shifts of the light-dark cycle, as in jet lag. For reducing symptoms and for speeding up resynchronization, several strategies have been suggested, including scheduled exercise, exposure to bright light, drugs, and especially exogenous melatonin administration. Restricted feeding schedules have shown to be powerful entraining signals for metabolic and hormonal daily cycles, as well as for clock genes in tissues and organs of the periphery. This study explored in a rat model of jet lag the contribution of exogenous melatonin or scheduled feeding on the re-entrainment speed of spontaneous general activity and core temperature after a 6-h phase advance of the light-dark cycle. In a first phase, the treatment was scheduled for 5 days prior to the phase shift, while in a second stage, the treatment was simultaneous with the phase advance of the light-dark cycle. Melatonin administration and especially scheduled feeding simultaneous with the phase shift improved significantly the re-entrainment speed. The evaluation of the free-running activity and temperature following the 5-day treatment proved that both exogenous melatonin and specially scheduled feeding accelerated re-entrainment of the SCN-driven general activity and core temperature, respectively, with 7, 5 days (p < 0.01) and 3, 3 days (p < 0.001). The present results show the relevance of feeding schedules as entraining signals for the circadian system and highlight the importance of using them as a strategy for preventing internal desynchrony.