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Circadian oscillations of cytosine modification in humans contribute to epigenetic variability, aging, and complex disease

ABSTRACT: Background: Maintenance of physiological circadian rhythm plays a crucial role in human health. Numerous studies have shown that disruption of circadian rhythm may increase risk for malignant, psychiatric, metabolic, and other diseases. Results: Extending our recent findings of oscillating cytosine modifications (osc-modCs) in mice, in this study, we show that osc-modCs are also prevalent in human neutrophils. Osc-modCs may play a role in both gene regulation, can explain parts of intra- and inter-individual epigenetic variation, and are signatures of aging. Finally, we show that osc-modCs are linked to three complex diseases and provide a new interpretation of cross-sectional epigenome-wide association studies. Conclusions: Our findings suggest that loss of balance between cytosine methylation and demethylation during the circadian cycle can be a potential mechanism for complex disease. Additional experiments, however, are required to investigate the possible involvement of confounding effects, such as hidden cellular heterogeneity. Circadian rhythmicity, one of the key adaptations of life forms on Earth, may contribute to frailty later in life.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83944 | GEO | 2018/12/04

REPOSITORIES: GEO

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Project description:Objective The objective of the current trial is to investigate the effect of perioperative sleep and circadian rhythm on the natural course of survival among patient diagnosed with colorectal cancer. Concurrently, outcome measures like depression, fatigue, quality of life, and co-morbidity will be measured continuously in the short-, intermediate- and long-term period following diagnosis. The a-priori hypothesis is that preoperative sleep and circadian disturbances is a prognostic marker of reduced overall survival. Likewise, preoperative sleep-wake disturbances at baseline are expected to result in overall universally reduced quality of life, increased depression and fatigue. Furthermore, development of sleep-wake disturbances in the postoperative period as compared to preoperative sleep-wake rhythm is expected to a prognostic marker of negative outcomes. Target and study population The study population are all patients diagnosed with colorectal cancer in Region Zealand recruited consecutively from the trial initiation until study end each patient with an intended 5 year follow-up period. All available cases will be included in the trial. Study design The study will be an observational prospective cohort study applying a longituditional repeated measure design. Exposures and outcomes of interest The primary outcomes in the trial are sleep and circadian outcomes measured via actigraphy in the perioperative period. Furthermore, cancer related survival and overall survival in the 5 year follow-up period is considered primary outcomes. Secondary outcomes consist of consecutively measured depression, fatigue, quality of life, follow-up treatment and co-morbidity. Exposure variables are primary related to the cancer, i.e. cancer stage, surgical treatment, oncological treatment, baseline co-morbidity and pharmacological treatment. Some of the secondary outcomes could be expected to serve as confounding or mediating factors. Meaningful control for confounding will in the analysis phase be cancer stage and baseline sleep-wake rhythm status. Sampling methods All available cases will be sought included in the trial. No formal sample size has been performed and continues inclusion into the trial will be performed during an 1,5 year period. Statistical analyses The relationship between overall survival and baseline sleep-wake rhythm will be investigated using survival statistics and/or multivariate logistic regression. Expected results The investigators expect to see a marked difference in overall survival among patients with sleep and circadian disturbances at baseline.

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Circadian oscillations of cytosine modification in humans contribute to epigenetic variability, aging, and complex disease

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