Proceedings of the National Academy of Sciences of the United States of AmericaNov 29, 2019

How Sleep, Wakefulness, and Internal Clocks Affect Daily Gene Activity and DNA Accessibility in the Mouse Thinking Areas

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Updated Mar 28, 2026

Abstract

A 6-hour in mice led to long-term changes in gene expression dynamics.

The interaction between sleep-wake processes and circadian rhythms influences gene regulation.
Rhythmic genes are primarily regulated by homeostatic processes, with some opposition from circadian control.
Sleep deprivation resulted in damped oscillations of core clock genes, indicating a direct impact on the molecular clock.
was highly dynamic during sleep deprivation, affecting gene expression.
Changes in gene expression are linked to the accessibility of enhancers and repressors rather than just promoters.
Serum response factor (SRF) was identified as a key regulator reflecting sleep pressure changes.

Simplified

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 in the cerebral cortex of mice over a 3-d period, including a 6-h (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, including/, 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. Arntl Bmal1

Key numbers

1,793

Differentially Accessible Peaks During

Number of chromatin peaks differentially accessible at ZT3 after 3 hours of .

2,098

Differentially Accessible Peaks at End of

Number of peaks differentially accessible at ZT6 after 6 hours of .

210

Genes with Long-Term Differential Expression

Number of genes differentially expressed after recovery from .

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How Sleep, Wakefulness, and Internal Clocks Affect Daily Gene Activity and DNA Accessibility in the Mouse Thinking Areas

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