Abstract
The circadian clock and aging are intertwined. Disruption to the normal diurnal rhythm accelerates aging and corresponds with telomere shortening. Telomere attrition also correlates with increase cellular senescence and incidence of chronic disease. In this report, we examined diurnal association of White Collar 2 (WC-2) in Neurospora and BMAL1 in zebrafish and mice and found that these circadian transcription factors associate with telomere DNA in a rhythmic fashion. We also identified a circadian rhythm in Telomeric Repeat-containing RNA (TERRA), a lncRNA transcribed from the telomere. The diurnal rhythm in TERRA was lost in the liver of Bmal1-/- mice indicating it is a circadian regulated transcript. There was also a BMAL1-dependent rhythm in H3K9me3 at the telomere in zebrafish brain and mouse liver, and this rhythm was lost with increasing age. Taken together, these results provide evidence that BMAL1 plays a direct role in telomere homeostasis by regulating rhythms in TERRA and heterochromatin. Loss of these rhythms may contribute to telomere erosion during aging.
Highlights
Circadian disruption affects a multitude of physiological processes and is implicated in the development of age-related diseases such as metabolic syndrome, cardiovascular disease and cancer [1]
While examining published White Collar-2 (WC-2) Chromatin immunoprecipitation (ChIP) followed by DNA sequencing (ChIP-seq) data, we observed that WC-2 appeared to localize to telomeres and localization was adjacent to Dicerindependent small interfering RNAs (Fig 1A) [33, 38]
We find that circadian clock transcription factors (BMAL1 in mammals and zebrafish, and WC-2 in Neurospora) are associated with telomeres and there is a rhythm in binding
Summary
Circadian disruption affects a multitude of physiological processes and is implicated in the development of age-related diseases such as metabolic syndrome, cardiovascular disease and cancer [1]. The circadian clock is built upon mechanistically conserved transcriptional feedback loops that generate physiological and behavioral rhythms coinciding with 24 h oscillations in light and dark cycles [2,3,4]. The regulatory loop is driven by the transcriptional activators CLOCK and BMAL1, which activates the expression of the negative elements Period (Per, Per, and Per3) and Cryptochrome (Cry and Cry). In Neurospora, a similar feedback loop is controlled by the transcriptional activators White Collar-1 (WC-1) and White Collar-2 (WC-2), which drive expression of the negative element frequency (frq). The interlocked and cooperative feedback loops of the circadian clock generate rhythms in clock-controlled genes (ccgs) to help maintain phase-specific outputs in biological processes [5].
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