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theses

The circadian clock governs gene expression for a large percentage of protein-coding genes in a tissue-specific manner. In this capacity, the clock maintains exquisite control of cell physiology and metabolism. The predominant regulatory mechanism of the clock is a transcriptional negative feedback loop that facilitates circadian-regulated facultative heterochromatin. The long-term consequence of disrupted diurnal rhythm, or mutations in core clock genes, is accelerated aging and an increased incidence of age-related diseases. However, the mechanisms underlying the precise pathways of the circadian clock and aging are not well understood. To understand the mechanisms of clock-regulated facultative heterochromatin in aging, I performed molecular experiments to examine the connections between BMAL1 and telomere homeostasis. I determined BMAL1 is associated with the telomeres and binding is conserved in zebrafish and mice. Expression of Telomere Repeat-containing RNA (TERRA), a long non-coding RNA (lncRNA) transcribed from the telomere has a diurnal rhythm in expression. In addition, there is a conserved rhythm in histone H3 lysine 9 tri-methylation (H3K9me3) at telomeres in zebrafish and mice. Given the rhythms in lncRNA and heterochromatin at the central clock gene(s) and telomeres, I set out to explore whether this was a genome-wide phenomenon, which may impact age-related redistribution of heterochromatin. I performed RNA-Seq and H3K9me3 ChIP-Seq on zebrafish brain tissue at different times and different ages. The computational analysis of sequencing data followed by molecular confirmation revealed that the core clock genes maintain rhythmic expression regardless of age, but most diurnal genes change expression with age. Coincidently, there are diurnal and age-related changes in H3K9me3 that coincide with the changes in gene expression. Taken together, this study suggests a model where age-related redistribution of rhythmic facultative heterochromatin is potentially mediated by changes in diurnal lncRNA expression creating a circadian-chromatin regulatory network in aging.

ETD_9368

Ph.D.

Includes bibliographical references

by Jinhee Park

doi:10.7282/t3-ce7y-sk60

ETD doctoral

The author owns the copyright to this work.