Abstract
BackgroundDisrupted diurnal rhythms cause accelerated aging and an increased incidence in age-related disease and morbidity. The circadian clock governs cell physiology and metabolism by controlling transcription and chromatin. The goal of this study is to further understand the mechanism of age-related changes to circadian chromatin with a focus on facultative heterochromatin and diurnal non-coding RNAs.ResultsWe performed a combined RNA-seq and ChIP-seq at two diurnal time-points for three different age groups to examine the connection between age-related changes to circadian transcription and heterochromatin in neuronal tissue. Our analysis focused on uncovering the relationships between long non-coding RNA (lncRNA) and age-related changes to histone H3 lysine 9 tri-methylation (H3K9me3), in part because the Period (Per) complex can direct facultative heterochromatin and models of aging suggest age-related changes to heterochromatin and DNA methylation. Our results reveal that lncRNAs and circadian output change dramatically with age, but the core clock genes remain rhythmic. Age-related changes in clock-controlled gene (ccg) expression indicate there are age-dependent circadian output that change from anabolic to catabolic processes during aging. In addition, there are diurnal and age-related changes in H3K9me3 that coincide with changes in transcription.ConclusionsThe data suggest a model where some age-related changes in diurnal expression are partially attributed to age-related alterations to rhythmic facultative heterochromatin. The changes in heterochromatin are potentially mediated by changes in diurnal lncRNA creating an interlocked circadian-chromatin regulatory network that undergoes age-dependent metamorphosis.
Highlights
Disrupted diurnal rhythms cause accelerated aging and an increased incidence in age-related disease and morbidity
We processed the overlapping transcripts (OT) with PLEK to predict potential natural antisense transcripts (NATs) [51] with the notion these may play a role in chromatin regulation
Further clustering of 17,702 transcripts into 8 groups based on expression revealed that expression of some long non-coding RNA (lncRNA) are restricted to specific times during embryo development, while others are restricted to adult fish (Additional file 3)
Summary
Disrupted diurnal rhythms cause accelerated aging and an increased incidence in age-related disease and morbidity. The circadian clock governs cell physiology and metabolism by controlling transcription and chromatin. More recent reports indicate circadian disruption contributes to increased morbidity [3] and diseases including; metabolic disorders [4,5,6], depressive disorders [7], cardiovascular disease [8], cancer [9], and advanced aging [10]. There are extensive age-related changes to clock-controlled genes (ccg) in the liver that correlate with age-related changes to metabolism which occurs with a change in acetylation [13, 14]. As a result of these reports and others, there is a growing appreciation of the connection among circadian disruption, advanced-aging and an increased incidence of age-related maladies, yet the mechanism underlying these remains cryptic.
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