The genome-wide landscape of DNA methylation and hydroxymethylation in response to sleep deprivation impacts on synaptic plasticity genes

Abstract

Sleep is critical for normal brain function and mental health. However, the molecular mechanisms mediating the impact of sleep loss on both cognition and the sleep electroencephalogram remain mostly unknown. Acute sleep loss impacts brain gene expression broadly. These data contributed to current hypotheses regarding the role for sleep in metabolism, synaptic plasticity and neuroprotection. These changes in gene expression likely underlie increased sleep intensity following sleep deprivation (SD). Here we tested the hypothesis that epigenetic mechanisms coordinate the gene expression response driven by SD. We found that SD altered the cortical genome-wide distribution of two major epigenetic marks: DNA methylation and hydroxymethylation. DNA methylation differences were enriched in gene pathways involved in neuritogenesis and synaptic plasticity, whereas large changes (>4000 sites) in hydroxymethylation where observed in genes linked to cytoskeleton, signaling and neurotransmission, which closely matches SD-dependent changes in the transcriptome. Moreover, this epigenetic remodeling applied to elements previously linked to sleep need (for example, Arc and Egr1) and synaptic partners of Neuroligin-1 (Nlgn1; for example, Dlg4, Nrxn1 and Nlgn3), which we recently identified as a regulator of sleep intensity following SD. We show here that Nlgn1 mutant mice display an enhanced slow-wave slope during non-rapid eye movement sleep following SD but this mutation does not affect SD-dependent changes in gene expression, suggesting that the Nlgn pathway acts downstream to mechanisms triggering gene expression changes in SD. These data reveal that acute SD reprograms the epigenetic landscape, providing a unique molecular route by which sleep can impact brain function and health.

Impact of traumatic brain injury on sleep structure, electrocorticographic activity and transcriptome in mice

“…More precisely, SD decreased the expression of Arc, Bdnf, Dnajb5, Fos, Homer1a and EphA4. This is in striking contrast with the acute effect of SD (i.e., gene expression measured immediately at the end of the 6 h SD), which increases the expression of most of these genes (Maret et al, 2007;Massart et al, 2014;Mongrain et al, 2010). SD also increased the expression of EfnA3 in the mouse cerebral cortex.…”

“…Bilateral sampling was performed to ensure sufficient biological material for measurements and to assess the combined impact of mTBI and SD on global brain function. RNA extraction, reverse transcription and quantitative PCR (qPCR) were performed similar to previously (El Helou et al, 2013;Massart et al, 2014). Briefly, RNA was extracted separately for the cerebral cortex and the hippocampus region using RNeasy Lipid Tissue Mini kit (Qiagen, Toronto, ON, Canada).…”

“…The fourth group (Sham-Control, n = 9) underwent a Sham surgery and were kept under an undisturbed sleep-wake cycle until sacrifice. SD was performed by gentle handling as previously performed (Franken et al, 1991;Massart et al, 2014).…”

“…ECoG/EMG electrode implantation was performed as detailed previously (El Helou et al, 2013;Massart et al, 2014), after undergoing either mTBI or Sham surgery. Briefly, mice were placed in a stereotaxic frame, and two gold-plated screws (1.1 mm diameter) served as ECoG electrodes and were screwed through the skull over the right cerebral hemisphere (anterior: 1.7 mm lateral to midline, 1.5 mm anterior to bregma; posterior: 1.7 mm lateral, 1.0 mm anterior to lambda).…”

La médecine du sommeil : 1965-2015

“…Ce volet de recherche est conduit plus spécifiquement par Valérie Mongrain. Ses travaux ont porté au départ sur la modulation des gènes de l'horloge circadienne chez la souris et, plus récem-ment, sur la régulation épigénétique de l'ADN après privation de sommeil (Massart et al, 2014). Ces études fondamentales sont essentielles à notre compréhension des causes et des conséquences des troubles du sommeil.…”