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

Abstract

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, including Arntl/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. circadian | sleep | gene expression | epigenetics | long-term effects A ccording to the 2-process model (1, 2), sleep regulation results from an interaction between a sleep homeostatic process and a circadian process often referred to as "process S" and "process C," respectively. The sleep homeostat tracks the need or pressure for sleep as it increases during wake and decreases during sleep, while the circadian process dictates the optimal time of day for sleep to occur. Their fine-tuned interaction assures optimal timing, duration, and quality of both wakefulness and sleep, and even minor changes in either of these processes or their alignment cause performance decrements and clinically significant sleep disruption (3,4).The circadian clock is described as self-sustained ∼24-h oscillations involved in a variety of physiological processes and behaviors, such as sleep (3,5). It is encoded molecularly through negative feedback loops involving the core clock genes, which are capable of generating oscillations in constant environmental conditions; that is, in the absence of periodically occurring time cues such as the light/dark cycle (6). However, this apparent autonomy does not inevitably imply that the expressi...

An essential role for MEF2C in the cortical response to loss of sleep

“…S3), including downregulation of Arntl, Clock and Npas2 and downregulation of a set of genes regulating circadian entrainment (MGI; GO:0009649). Taken together, these data are consistent with an SD-induced attenuation and 25 destabilization of circadian-mediated gene expression and confirm recent observations using an RNAseq assessment in time series together with SD (Hor et al, 2019).…”

“…These results are consistent with and extend those from a previous study using microarrays (Cirelli, Gutierrez, & Tononi, 2004) that lead to a conclusion, "… that sleep, far from being a quiescent state of global inactivity, may actively favor specific cellular functions". 30 Recently, similar findings were reported in a RNAseq analysis from C57BL/6J whole cortex and a "gentle handling" method of SD (Hor et al, 2019).…”

Phosphorylation Hypothesis of Sleep

“…The model successfully characterizes the different sleep phenotypes among inbred mice ( Franken et al, 2001 ) and human individuals ( Rusterholz et al, 2010 ). Furthermore, the model was also applied to classify the dynamics of the gene expression profile ( Hor et al, 2019 ).…”

Circadian rhythms and obesity: Timekeeping governs lipid metabolism

“…For example, gene expression, transcription factors, signaling pathways, hormone secretion, energy metabolism, growth, and behavior are rhythmically coordinated by the circadian system. [7][8][9] Predictably, the genetic or environmental disruption of the circadian clock is characterized by high prevalence of diseases or exacerbated pathological status. [10][11][12] In the past few years, increasing experimental evidence has shown a strong interaction between the circadian clock and lipid dysmetabolism or obesity, but the mechanisms by which the circadian clock regulates of lipid metabolism have not been fully elucidated.…”