Sleep–wake-driven and circadian contributions to daily rhythms in gene expression and chromatin accessibility in the murine cortex

The timing and duration of sleep results from the interaction between a homeostatic sleep–wake-driven process and a periodic circadian process, and involves changes in gene regulation and expression. Unraveling the contributions of both processes and their interaction to transcriptional and epigenomic regulatory dynamics requires sampling over time under conditions of unperturbed and perturbed sleep. We profiled mRNA expression and chromatin accessibility in the cerebral cortex of mice over a 3-d period, including a 6-h sleep deprivation (SD) on day 2. We used mathematical modeling to integrate time series of mRNA expression data with sleep–wake history, which established that a large proportion of rhythmic genes are governed by the homeostatic process with varying degrees of interaction with the circadian process, sometimes working in opposition. Remarkably, SD caused long-term effects on gene-expression dynamics, outlasting phenotypic recovery, most strikingly illustrated by a damped oscillation of most core clock genes, includingArntl/Bmal1, suggesting that enforced wakefulness directly impacts the molecular clock machinery. Chromatin accessibility proved highly plastic and dynamically affected by SD. Dynamics in distal regions, rather than promoters, correlated with mRNA expression, implying that changes in expression result from constitutively accessible promoters under the influence of enhancers or repressors. Serum response factor (SRF) was predicted as a transcriptional regulator driving immediate response, suggesting that SRF activity mirrors the build-up and release of sleep pressure. Our results demonstrate that a single, short SD has long-term aftereffects at the genomic regulatory level and highlights the importance of the sleep–wake distribution to diurnal rhythmicity and circadian processes.

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Simple and complex interactions between sleep-wake driven and circadian processes shape daily genome regulatory dynamics in the mouse

10.1101/677807 ◽

2019 ◽

Author(s):

Charlotte N. Hor ◽

Jake Yeung ◽

Maxime Jan ◽

Yann Emmenegger ◽

Jeffrey Hubbard ◽

...

Keyword(s):

Gene Expression ◽

Sleep Deprivation ◽

Mrna Expression ◽

Clock Genes ◽

Poor Quality ◽

Chromatin Accessibility ◽

Time Of Day ◽

Long Term Effects ◽

Regulatory Dynamics

AbstractThe timing and duration of sleep results from the interaction between a sleep-wake driven, or homeostatic, process (S) and a circadian process (C), and involves changes in gene expression and genomic regulation. Unraveling the respective contributions of S and C, and their interaction, to transcriptional and epigenomic regulatory dynamics requires sampling over time under unperturbed conditions and conditions of perturbed sleep. Here, we profiled mRNA expression and chromatin accessibility in the cerebral cortex of mice over a three-day period, including a 6-hour sleep deprivation (SD) on day two. Mathematical modeling established that a large proportion of rhythmic genes are actually governed by Process S with varying degrees of interaction with Process C, sometimes working in opposition. Remarkably, SD causes long-term effects on gene expression dynamics, outlasting phenotypic recovery, most strikingly illustrated by a dampening of the oscillation of most core clock genes, including Bmal1, suggesting that enforced wakefulness directly impacts the molecular clock machinery. Chromatin accessibility proved highly plastic and dynamically affected by SD. Distal regions, rather than promoters, display dynamics corresponding to gene transcription, implying that changes in mRNA expression result from constantly accessible promoters under the influence of distal enhancers or repressors. Srf was predicted as a transcriptional regulator driving immediate response, suggesting that Srf activity mirrors the build-up and release of sleep pressure. Our results demonstrate that a single, short SD has long-term aftereffects at the genomic regulatory level. Such effects might accumulate with repeated sleep restrictions, thereby contributing to their adverse health effects.Significance statementWhen and how long we sleep is determined by the time-of-day and how long we have been awake, which are tracked molecularly by a circadian and a sleep-wake driven process, respectively. We measured the long-term consequences of a short-term sleep deprivation (SD) on gene expression and regulation in the mouse brain, and used mathematical models to determine the relative contributions of the circadian and sleep-wake driven processes. We find that many genes, including most of the genes that constitute the molecular circadian clock, are perturbed by SD long after the mice ceased showing behavioral signs of sleep loss. Our results have implications for human health, given the high prevalence of insufficient and poor quality sleep in our contemporary society.

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Clock genes in calendar cells as the basis of annual timekeeping in mammals--a unifying hypothesis

Journal of Endocrinology ◽

10.1677/joe.0.1790001 ◽

2003 ◽

Vol 179 (1) ◽

pp. 1-13 ◽

Cited By ~ 149

Author(s):

GA Lincoln ◽

H Andersson ◽

A Loudon

Keyword(s):

Gene Expression ◽

Molecular Mechanism ◽

Clock Genes ◽

Prolactin Secretion ◽

Secretory Cells ◽

Dark Phase ◽

Pars Tuberalis ◽

Cry Protein ◽

Wide Range

Melatonin-based photoperiod time-measurement and circannual rhythm generation are long-term time-keeping systems used to regulate seasonal cycles in physiology and behaviour in a wide range of mammals including man. We summarise recent evidence that temporal, melatonin-controlled expression of clock genes in specific calendar cells may provide a molecular mechanism for long-term timing. The agranular secretory cells of the pars tuberalis (PT) of the pituitary gland provide a model cell-type because they express a high density of melatonin (mt1) receptors and are implicated in photoperiod/circannual regulation of prolactin secretion and the associated seasonal biological responses. Studies of seasonal breeding hamsters and sheep indicate that circadian clock gene expression in the PT is modulated by photoperiod via the melatonin signal. In the Syrian and Siberian hamster PT, the high amplitude Per1 rhythm associated with dawn is suppressed under short photoperiods, an effect that is mimicked by melatonin treatment. More extensive studies in sheep show that many clock genes (e.g. Bmal1, Clock, Per1, Per2, Cry1 and Cry2) are expressed in the PT, and their expression oscillates through the 24-h light/darkness cycle in a temporal sequence distinct from that in the hypothalamic suprachiasmatic nucleus (central circadian pacemaker). Activation of Per1 occurs in the early light phase (dawn), while activation of Cry1 occurs in the dark phase (dusk), thus photoperiod-induced changes in the relative phase of Per and Cry gene expression acting through PER/CRY protein/protein interaction provide a potential mechanism for decoding the melatonin signal and generating a long-term photoperiodic response. The current challenge is to identify other calendar cells in the central nervous system regulating long-term cycles in reproduction, body weight and other seasonal characteristics and to establish whether clock genes provide a conserved molecular mechanism for long-term timekeeping.

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Caffeine induces both short‐term and long‐term effects on gene expression and DNA methylation in the mouse heart (542.3)

The FASEB Journal ◽

10.1096/fasebj.28.1_supplement.542.3 ◽

2014 ◽

Vol 28 (S1) ◽

Author(s):

Christopher Wendler ◽

Ryan Poulsen ◽

Xiefan Fang

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Mouse Heart ◽

Long Term Effects ◽

Short Term

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Long Term Effects of Neonatal Hypoglycemia on Muscarinic Receptor Function in the Cerebellum

Journal of Pediatrics & Neonatal Biology ◽

10.33140/jpnb.02.01.03 ◽

2017 ◽

Vol 2 (1) ◽

Keyword(s):

Gene Expression ◽

Signaling Pathways ◽

Muscarinic Receptor ◽

Receptor Subtype ◽

Receptor Function ◽

Long Term Effects ◽

Neonatal Hypoglycemia ◽

Neonatal Stress ◽

Old Rats

Neonatal stress conditions like hypoglycemia cause brain damage by affecting various signaling pathways thereby causing long term effects on brain functions. A proper understanding of the signaling pathways affected by this stress will help to devise better neonatal care. The focus of the current study was to evaluate the effect of neonatal hypoglycemic insult on cerebellar metabotropic cholinergic receptor function in one month old rats. The receptor analysis of cholinergic muscarinic receptors were done by radioreceptor assays and gene expression was analysed using Real Time PCR. Neonatal hypoglycemia significantly reduced (p<0.001) the cerebellar muscarinic receptor density with a down regulation (p<0.001) of muscarinic M3 receptor subtype gene expression in one month old rats. Both muscarinic M1 and M2 receptor subtype expression were not significantly altered. The catabolic enzyme in acetyl choline metabolism- acetylcholine esterase – showed a significant (p<0.001) up regulation with no siginificant change in the anabolic enzyme – choline acetyl transferase, signifying a change in the turnover ratio. Targeting these pathways at different levels can be exploited to devise better treatment for neonatal stress management and also for diseases with impaired insulin secretion such as diabetes.

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The long-term effects of exposure to ionising radiation on gene expression in mice

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis ◽

10.1016/j.mrfmmm.2020.111723 ◽

2020 ◽

Vol 821 ◽

pp. 111723

Author(s):

Ayman Jafer ◽

Nicolas Sylvius ◽

Adeolu B. Adewoye ◽

Yuri E. Dubrova

Keyword(s):

Gene Expression ◽

Ionising Radiation ◽

Long Term Effects

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Developmental conditions modulate DNA methylation at the glucocorticoid receptor gene with cascading effects on expression and corticosterone levels in zebra finches

Scientific Reports ◽

10.1038/s41598-019-52203-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Blanca Jimeno ◽

Michaela Hau ◽

Elena Gómez-Díaz ◽

Simon Verhulst

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Glucocorticoid Receptor ◽

Early Life ◽

Receptor Gene ◽

Regulatory Region ◽

Long Term Effects ◽

Glucocorticoid Receptor Gene ◽

Developmental Conditions

Abstract Developmental conditions can impact the adult phenotype via epigenetic changes that modulate gene expression. In mammals, methylation of the glucocorticoid receptor gene Nr3c1 has been implicated as mediator of long-term effects of developmental conditions, but this evidence is limited to humans and rodents, and few studies have simultaneously tested for associations between DNA methylation, gene expression and phenotype. Adverse environmental conditions during early life (large natal brood size) or adulthood (high foraging costs) exert multiple long-term phenotypic effects in zebra finches, and we here test for effects of these manipulations on DNA methylation and expression of the Nr3c1 gene in blood. Having been reared in a large brood induced higher DNA methylation of the Nr3c1 regulatory region in adulthood, and this effect persisted over years. Nr3c1 expression was negatively correlated with methylation at 2 out of 8 CpG sites, and was lower in hard foraging conditions, despite foraging conditions having no effect on Nr3c1 methylation at our target region. Nr3c1 expression also correlated with glucocorticoid traits: higher expression level was associated with lower plasma baseline corticosterone concentrations and enhanced corticosterone reactivity. Our results suggest that methylation of the Nr3c1 regulatory region can contribute to the mechanisms underlying the emergence of long-term effects of developmental conditions in birds, but in our system current adversity dominated over early life experiences with respect to receptor expression.

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