What are microarrays teaching us about sleep?

University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Trends in Molecular Medicine (Impact Factor: 9.45). 02/2009; 15(2):79-87. DOI: 10.1016/j.molmed.2008.12.002
Source: PubMed


Many fundamental questions about sleep remain unanswered. The presence of sleep across phyla suggests that it must serve a basic cellular and/or molecular function. Microarray studies, performed in several model systems, have identified classes of genes that are sleep-state regulated. This has led to the following concepts: first, a function of sleep is to maintain synaptic homeostasis; second, sleep is a stage of macromolecule biosynthesis; third, extending wakefulness leads to downregulation of several important metabolic pathways; and, fourth, extending wakefulness leads to endoplasmic reticulum stress. In human studies, microarrays are being applied to the identification of biomarkers for sleepiness and for the common debilitating condition of obstructive sleep apnea.

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Available from: Keith Shockley, Jul 09, 2014
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    • "Microarrays, specifically, have become widely used in sleep research to evaluate and compare transcriptomic profiles of sleep-wake and sleep deprived states with an initial emphasis on characterizing the sleep and awake states. Together, these studies have yielded thousands of candidate genes involved in sleep homeostasis and/or function (Terao et al. 2003a; Terao et al. 2003b; Cirelli et al. 2006; Terao et al. 2006; Mackiewicz et al. 2007; Maret et al. 2007; Kilduff et al. 2008; Mackiewicz et al. 2009; Thompson et al. 2010; Veasey 2010; Datta et al. 2011; Mongrain et al. 2011). Many of these genes are now considered sleep-state regulated and belong to classes of genes involved in specific cellular functions, such as synaptic maintenance and plasticity (Taishi et al. 2001; Nelson et al. 2004; Maret et al. 2007; Das et al. 2008; Mallick and Singh 2011; Tadavarty et al. 2011; Franco-Perez et al. 2012; Singh et al. 2012; Volkow et al. 2012), metabolism (Basheer et al. 2001; Kong et al. 2002; Mackiewicz et al. 2003; Nikonova et al. 2010; Petit et al. 2010; Everson and Szabo 2011; Martins et al. 2011; Barf et al. 2012), stress response (Meerlo et al. 2002; Terao et al. 2003b; Sgoifo et al. 2006; Brown and Naidoo 2010; Kalinchuk et al. 2010), and neuroprotection (Weil et al. 2009; Mongrain et al. 2010; Dattilo et al. 2011; Wisor et al. 2011). "
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    ABSTRACT: Epidemiological studies show a positive association between adequate sleep and good health. Further, disrupted sleep may increase the risk for CNS diseases, such as stroke and Alzheimer’s disease. However, there has been limited progress in determining how sleep is linked to brain health or how sleep disruption may increase susceptibility to brain insult and disease. Animal studies can aid in understanding these links. In reviewing the animal literature related to the effects of sleep disruption on the brain, we found most of the work was directed toward investigating and characterizing the role of various brain areas or structures in initiating and regulating sleep. In contrast, limited effort has been directed towards understanding how sleep disruption alters the brain’s health or susceptibility to insult. We also note many current studies have determined the changes in the brain following compromised sleep by examining, for example, the brain transcriptome or to a more limited extent the proteome. However, these studies have utilized almost exclusively total sleep deprivation (e.g., 24 out of 24 hours) paradigms or single short periods of limited acute sleep deprivation (e.g., 3 out of 24 hours). While such strategies are beneficial in understanding how sleep is controlled, they may not have much translational value for determining links between sleep and brain health or for determining how sleep disruption may increase brain susceptibility to insult. Surprisingly, few studies have determined how the duration and recurrence of sleep deprivation influence the effects seen after sleep deprivation. Our aim in this review was to identify relevant rodent studies from 1980 through 2012 and analyze those that use varying durations of sleep deprivation or restriction in their effort to evaluate the effects of sleep deprivation on the brain transcriptome and to a more limited extent the proteome. We examined how differences in the duration of sleep deprivation affect gene and protein expression to better understand the full consequences of repeated sleep disruption on the brain. Future research needs to consider and emphasize how the type and extent of the sleep deprivation exposure impacts the conclusions reached concerning the influence of sleep disruption on the brain. We identified relevant studies between 1980 and 2012 by searching the electronic databases of PubMed, Medline (Ovid), Embase (Ovid), and Web of Science using the terms “sleep” AND “disrupt”, “deprivation”, “restrict”, “fragment”, “loss”, “disturb”, “disorder”, “dysfunction”, “brain”, “cortex”, striatum”, hypothalamus”, “hippocampus”, “gene”, “protein”, “genomics”, “proteomics”, “polymerase chain reaction”, “pcr”, “microarray”, “molecular”, “rodent” “rat”, “rats”, “mouse”, “mice”. All searches were limited to rodent studies in English and the reference lists of retrieved articles were searched for additional pertinent studies.
    Full-text · Article · Dec 2014 · SpringerPlus
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    • "The UPR was first connected to the molecular response to sleep deprivation in the fly brain [30] and has since been found to be up-regulated by sleep deprivation in different brain regions across multiple species (for review, see [14]). In the brain, the differential expression of molecular chaperones and the UPR between sleep and sleep deprivation is maintained in mice after adrenalectomy [31] and is thus not the result of HPA axis stress. "
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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.
    Full-text · Article · May 2013 · BMC Genomics
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    • "The overall finding of 4 genes agreeing, and two more agreeing in direction of change, particularly in a separate set of subjects measuring a different type of molecule, appears to constitute reasonable corroboration. Additionally, prior microarray SD studies in brain tissue [50], [54], [56], [60] also validate these findings (noted in Table S1; see [63] for discussion on limitations of this approach). "
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    ABSTRACT: Many aging changes seem similar to those elicited by sleep-deprivation and psychosocial stress. Further, sleep architecture changes with age suggest an age-related loss of sleep. Here, we hypothesized that sleep deprivation in young subjects would elicit both stress and aging-like transcriptional responses. F344 rats were divided into control and sleep deprivation groups. Body weight, adrenal weight, corticosterone level and hippocampal CA1 transcriptional profiles were measured. A second group of animals was exposed to novel environment stress (NES), and their hippocampal transcriptional profiles measured. A third cohort exposed to control or SD was used to validate transcriptional results with Western blots. Microarray results were statistically contrasted with prior transcriptional studies. Microarray results pointed to sleep pressure signaling and macromolecular synthesis disruptions in the hippocampal CA1 region. Animals exposed to NES recapitulated nearly one third of the SD transcriptional profile. However, the SD-aging relationship was more complex. Compared to aging, SD profiles influenced a significant subset of genes. mRNA associated with neurogenesis and energy pathways showed agreement between aging and SD, while immune, glial, and macromolecular synthesis pathways showed SD profiles that opposed those seen in aging. We conclude that although NES and SD exert similar transcriptional changes, selective presynaptic release machinery and Homer1 expression changes are seen in SD. Among other changes, the marked decrease in Homer1 expression with age may represent an important divergence between young and aged brain response to SD. Based on this, it seems reasonable to conclude that therapeutic strategies designed to promote sleep in young subjects may have off-target effects in the aged. Finally, this work identifies presynaptic vesicular release and intercellular adhesion molecular signatures as novel therapeutic targets to counter effects of SD in young subjects.
    Full-text · Article · Jul 2012 · PLoS ONE
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