DNA Methylation & Insufficient Sleep
A distinctive DNA methylation pattern in insufficient sleep
Lack of sleep and sleep disturbances are extremely common in the general population. According to the population-based surveys conducted in Finland, up to one-third of the general adult population experiences occasional difficulties in sleep, and almost one-fourth reported sleeping 6 hours or less per night.
The symptoms of insomnia have become widespread, especially in the working population: in 2007, a report based in Finland revealed that insomnia-related symptoms were frequent among 9% of workers and occasional in up to 45.3%.
Night and early morning shift work is a common source of insufficient sleep, since it leads to circadian misalignments, misbalances homeostasis, and truncates total sleep time by 1–4 hours. The detrimental effects of shift work on sleep can result in shift work disorder (SWD) – a medical condition characterized by complaints of excessive sleepiness and/or insomnia as primary symptoms, accompanied by a reduction in sleep duration during the working period. It is a common condition affecting over one-third of shift workers.
The effect of sleep deprivation on the transcriptome and methylome has previously been studied both in experimental animal models and in selected samples. Sleep deprivation induces notable changes in the brain transcriptome of rats, affecting protein synthesis, synaptic plasticity, and metabolism. For example, Archer et al. found a reduction of rhythmic transcripts and major changes in the transcriptome once sleep was mistimed.
Simply missing a single night’s sleep alters both the transcriptional and the DNA methylation profiles of core circadian clock genes.
Indeed, Bhatti et al. found a significant decrease in average methylation among the nightshift workers compared to the methylation profiles of dayshift workers.
Despite the extensive ‘omics’ studies conducted in human cohorts during the last decades, the biological mechanisms underlying the negative consequences of chronic lack of sleep in workers are not fully understood and the inter-individual variation of such consequences is known to be quite large. Our previous work focused on intrinsic genetic risk factors for intolerance to shift work and found an association between job-related exhaustion and a variant downstream of the melatonin receptor 1A gene with a proposed mechanism of changes in DNA methylation at the gene promoter when exposed to the risk environment (shift work).
In this study, we investigated DMPs in blood leukocytes that reflect the systemic stress triggered by insufficient sleep in two complementary samples of cases and controls from (i) individuals selected from a community-based sample (DILGOM, a sub-study of the population-based FINRISK) and from (ii) an occupational cohort of shift workers (Airline).
In (i), cases were selected based on their self-reported evaluation of sleep insufficiency, meaning seldom or hardly ever sleeping enough. In (ii), cases were selected based on the presence of SWD symptoms specifically during shift work periods: symptoms of insomnia, sleepiness, and objectively measured reduction in total sleep time.
Short sleep duration or insomnia may lead to an increased risk of various psychiatric and cardio-metabolic conditions. Since DNA methylation plays a critical role in the regulation of gene expression, studies of differentially methylated positions (DMPs) might be valuable for understanding the mechanisms underlying insomnia.
We performed a cross-sectional genome-wide analysis of DNA methylation in relation to self-reported insufficient sleep in individuals from a community-based sample (79 men, aged 39.3 ± 7.3), and in relation to shifting work disorder in an occupational cohort (26 men, aged 44.9 ± 9.0).
The analysis of DNA methylation data revealed that genes corresponding to selected DMPs form a distinctive pathway: "Nervous System Development" (FDR P value < 0.05).
We found that 78% of the DMPs were hypomethylated in cases in both cohorts, suggesting that insufficient sleep may be associated with loss of DNA methylation. A karyoplot revealed clusters of DMPs at various chromosomal regions, including 12 DMPs on chromosome 17, previously associated with Smith-Magenis syndrome, a rare condition comprising disturbed sleep and inverse circadian rhythm.
Our findings give novel insights into the DNA methylation patterns associated with sleep loss, possibly modifying processes related to neuroplasticity and neurodegeneration. Future prospective studies are needed to confirm the observed associations.