Light-dark oscillations in the lung transcriptome: Implications for lung homeostasis, repair, metabolism, disease, and drug action

Dept. of Biological Sciences, 107 Hochstetter Hall, State Univ. of New York at Buffalo, Buffalo, NY 14260, USA.
Journal of Applied Physiology (Impact Factor: 3.06). 03/2011; 110(6):1732-47. DOI: 10.1152/japplphysiol.00079.2011
Source: PubMed


Diurnal-nocturnal, or circadian-like, rhythms are 24-h variations in biological processes, evolved for the efficient functioning of living organisms. Such oscillations and their regulation in many peripheral tissues are still unclear. In this study, we used Affymetrix gene chips in a rich time-series experiment involving 54 animals killed at 18 time points within the 24-h cycle to examine light-dark cycle patterns of gene expression in rat lungs. Data mining identified 646 genes (represented by 1,006 probe sets) showing robust oscillations in expression in lung that were parsed into 8 distinct temporal clusters. Surprisingly, more than two-thirds of the probe sets showing cyclic expression peaked during the animal's light/inactive period. Six core clock genes and nine clock-related genes showed rhythmic oscillations in their expression in lung. Many of the genes that peaked during the inactive period included genes related to extracellular matrix, cytoskeleton, and protein processing and trafficking, which appear to be mainly involved in the repair and remodeling of the organ. Genes coding for growth factor ligands and their receptors, which play important roles in maintaining normal lung function, also showed rhythmic expression. In addition, genes involved in the metabolism and transport of endogenous compounds, xenobiotics, and therapeutic drugs, along with genes that are biomarkers or potential therapeutic targets for many lung diseases, also exhibited 24-h cyclic oscillations, suggesting an important role for such rhythms in regulating various aspects of the physiology and pathophysiology of lung.

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    • "A recent study has shown that in the lung, more than two-thirds of the probe sets showing cyclic expression peaked during the animal's light/inactive period . Many of the genes that peaked during the inactive period included genes related to extracellular matrix, cytoskeleton, and macromolecular trafficking, which appear to be mainly involved in the turnover and remodelling of the organ (Sukumaran et al. 2011). At the same time, light triggers coordinated cyclic AMP-response element-binding protein expression and mTOR activation in the suprachiasmatic nucleus (SCN) and neurons (Cao et al. 2008). "
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    ABSTRACT: The circadian clock coordinates the internal physiology to increase the homeostatic capacity thereby providing both a survival advantage to the system and an optimization of energy budgeting. Multiple-oscillator circadian mechanisms are likely to play a role in regulating human health and may contribute to the aging process. Our aim is to give an overview of how the central clock in the hypothalamus and peripheral clocks relate to aging and metabolic disorders, including hyperlipidemia and hyperglycemia. In particular, we unravel novel putative mechanisms to link circadian clocks to healthy aging. This review may lead to the design of large-scale interventions to help people stay healthy as they age by adjusting daily activities, such as feeding behavior, and or adaptation to age-related changes in individual circadian rhythms.
    Journal of Neural Transmission 12/2013; DOI:10.1007/s00702-013-1128-4 · 2.40 Impact Factor
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    • "The consequences of frequent jetlag have serious effects on health, including sleep disorders, chronic memory deficits, obesity, diabetes, and other metabolic diseases [7] [12], as well as the development of cancer [13]. Various chronomic studies [6–8, 13–15] seek to understand the endogenous and exogenous mechanisms of synchronization and desynchronization. "
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    ABSTRACT: Bioinformatics and other well-established sciences, such as molecular biology, genetics, and biochemistry, provide a scientific approach for the analysis of data generated through "omics" projects that may be used in studies of chronobiology. The results of studies that apply these techniques demonstrate how they significantly aided the understanding of chronobiology. However, bioinformatics tools alone cannot eliminate the need for an understanding of the field of research or the data to be considered, nor can such tools replace analysts and researchers. It is often necessary to conduct an evaluation of the results of a data mining effort to determine the degree of reliability. To this end, familiarity with the field of investigation is necessary. It is evident that the knowledge that has been accumulated through chronobiology and the use of tools derived from bioinformatics has contributed to the recognition and understanding of the patterns and biological rhythms found in living organisms. The current work aims to develop new and important applications in the near future through chronobiology research.
    The Scientific World Journal 09/2013; 2013(3676):153839. DOI:10.1155/2013/153839 · 1.73 Impact Factor
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    • "The same classes of transcripts that were synchronized by sleep have been identified among the most enriched annotations describing circadian transcripts in the rat lung [73]. The ability for sleep to act as a synchronizing cue for peripheral oscillators suggests that sleep may have a role in coordinating the physiology of peripheral tissues and matching that physiology to behavioral rhythms. "
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    ABSTRACT: Background Many have assumed that the primary function of sleep is for the brain. We evaluated the molecular consequences of sleep and sleep deprivation outside the brain, in heart and lung. Using microarrays we compared gene expression in tissue from sleeping and sleep deprived mice euthanized at the same diurnal times. Results In each tissue, nearly two thousand genes demonstrated statistically significant differential expression as a function of sleep/wake behavioral state. To mitigate the influence of an artificial deprivation protocol, we identified a subset of these transcripts as specifically sleep-enhanced or sleep-repressed by requiring that their expression also change over the course of unperturbed sleep. 3% and 6% of the assayed transcripts showed “sleep specific” changes in the lung and heart respectively. Sleep specific transcripts in these tissues demonstrated highly significant overlap and shared temporal dynamics. Markers of cellular stress and the unfolded protein response were reduced during sleep in both tissues. These results mirror previous findings in brain. Sleep-enhanced pathways reflected the unique metabolic functions of each tissue. Transcripts related to carbohydrate and sulfur metabolic processes were enhanced by sleep in the lung, and collectively favor buffering from oxidative stress. DNA repair and protein metabolism annotations were significantly enriched among the sleep-enhanced transcripts in the heart. Our results also suggest that sleep may provide a Zeitgeber, or synchronizing cue, in the lung as a large cluster of transcripts demonstrated systematic changes in inter-animal variability as a function of both sleep duration and circadian time. Conclusion Our data support the notion that the molecular consequences of sleep/wake behavioral state extend beyond the brain to include peripheral tissues. Sleep state induces a highly overlapping response in both heart and lung. We conclude that sleep enhances organ specific molecular functions and that it has a ubiquitous role in reducing cellular metabolic stress in both brain and peripheral tissues. Finally, our data suggest a novel role for sleep in synchronizing transcription in peripheral tissues.
    BMC Genomics 05/2013; 14(1):362. DOI:10.1186/1471-2164-14-362 · 3.99 Impact Factor
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