Year: 2017
Type: dissertation
Abstract: Circadian rhythmicity governs a remarkable array of fundamental biological functions in eukaryotes which is mediated by cyclical metabolomic, transcriptomic, and proteomic activities. Histone modifications and other epigenetic factors are also involved in the circadian machinery; however, despite significant efforts detection of circadian DNA (cytosine) modification has remained elusive. In this study, we aimed to document and explore the features of circadian oscillations of cytosine modifications. We discovered that a substantial number of cytosines show a circadian pattern in their modification status in mouse liver and lung, as well as human neutrophils. Furthermore, we found that circadian oscillations of cytosine modification are linked to circadian transcription. Our findings also indicate that circadian oscillations explain a portion of the epigenetic variation which traditionally has been called random or stochastic. There are numerous clinical and molecular studies showing strong associations between declining circadian rhythmicity and aging, but the molecular underpinnings of this association are not clear. Since epigenetic alterations accompany aging, we aimed to investigate the relationship between daily cytosine modification oscillations and the aging epigenome. We discovered that cytosines which exhibited circadian epigenetic oscillations significantly overlapped with the cytosines exhibiting age-related modification changes. Furthermore, the amplitude of these oscillations strongly correlated with the degree of age-dependent changes. Finally, the day or night timing of circadian peaks were accurate predictors of whether a specific cytosine will lose or gain modification in the aging tissue. Epigenetic changes, circadian dysregulation, and age have all been implicated in a number of complex diseases. Consequently, our third aim was to examine the contributions of DNA modification oscillations to the epigenetic changes identified in epigenome-wide association studies of complex disease. We tested leukemia, Alzheimerâ s disease, and schizophrenia, and in all cases, we found a significant overlap between cytosines exhibiting daily oscillations and those identified in disease studies. We therefore propose that circadian epigenetic oscillations may contribute not only to aging but also to disease. Based on our findings, further studies are warranted for a more complete understanding of how evolutionary advantageous processes like circadian rhythmicity can also mediate an organismâ s demise.
Source: TSpace (University of Toronto)
Author: Sasha B. Ebrahimi
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3090112206