Understanding rhythmic gene regulatory mechanisms in the mammalian circadian system

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Summary Circadian rhythms are biological, physiological, and behavioral processes that enable organisms to respond to the environmental changes caused by the rotation of the Earth. Interestingly, recent data started to shed light into the impact of aging on circadian rhythms. For example, circadian processes, such as melatonin secretion and onset of sleep, are phase-advanced in the circadian cycle as humans age. Moreover, the number of rhythmically expressed genes is reduced by 23% in old mouse liver compared to young mouse liver. Furthermore, nearly half of mRNA expressed rhythmically in old mouse liver are not expressed rhythmically in young mouse liver. These data clearly indicate that the aging process changes the molecular mechanisms that drive rhythmic mRNA expression. However, it remains unclear how aging alters the number and identity of rhythmically expressed mRNAs. The goal of this proposal is to understand how the molecular mechanisms that regulate rhythmic gene expression are altered with age and what impact aging has on the circadian cycle. Successful accomplishment of the proposed project will uncover age-related changes to the mechanisms that drive circadian gene expression that are thought to play key roles in driving and maintaining circadian rhythms of various downstream biological processes. For an mRNA to be rhythmically expressed; synthesis, degradation, or a combination of the two must be rhythmic. Additionally, the average mRNA half-life must be short enough for RNA to be newly synthesized each day. In Aim 1, we will experimentally measure circadian changes of mRNA expression, mRNA synthesis and degradation rates both in young and old mouse fibroblasts to evaluate which of these processes is most susceptible to age-related changes in driving rhythmic gene expression. In Aim 2, we will bioinformatically measure circadian changes of mRNA expression, mRNA synthesis degradation rates in fly brain by leveraging circadian RNA-seq datasets that are publicly available. Identification of age-related changes in driving circadian gene expression can ultimately help us develop diagnostic tools and intervention strategies to mitigate circadian disturbances with age. Modern lifestyles contain many stimuli that disrupt the core-clock mechanism such as bright light at night from phones, jet-lag, and night shift work. It is critical that we understand how the mechanisms that drive circadian rhythms change with age to prevent circadian dysregulation that may be exacerbated with age.