Saturday, December 21, 2024
12/21/2024
ABSTRACT Circadian clocks are cell-autonomous timekeepers that generate ~24-hour oscillations in gene expression and control rhythms in almost all aspects of our behavior and physiology, including sleep- wake cycles, metabolism, and immunity. Almost every cell in the human body has a clock and dysregulation of clocks have been implicated in many human pathologies such as diabetes, cancer, and neurodegenerative diseases. Although past studies, primarily using genetic screens and biochemical assays, have outlined the genetic basis of circadian rhythms, very little is known about how circadian clocks are organized and regulated at the subcellular level in an intact organism. Using Drosophila clock neurons as a model system, my lab has recently made the surprising discovery that clock neurons possess a complex internal organization where clock proteins, genes, and mRNAs are strategically localized to specific subcellular compartments so that cellular events can occur at the right time and the right place. Specifically, we have discovered that clock proteins and genes are organized into nuclear condensates at the nuclear periphery during the circadian repression phase to enable transcriptional co- repression. More recently, our studies revealed that clock mRNAs and proteins are localized to the perinuclear cytoplasmic region, which is vital for the post-transcriptional regulation of clock mRNAs and for generating ~24-h circadian rhythms. My laboratory will build upon these discoveries to achieve a mechanistic understanding of the spatiotemporal mechanisms that govern circadian rhythms by developing novel tools as well as harnessing the power of high-resolution live imaging, genetics, proteomics, functional genomics, and behavior assays. First, we will utilize a novel proximity labeling approach that we developed for identifying interaction partners of Period, a core clock protein, over the circadian cycle to gain a deeper understanding of circadian regulation at the molecular level. Second, we will investigate circadian genome organization in clock neuron nuclei using both imaging and sequencing- based methods and determine the underlying molecular mechanisms to understand the role of nuclear architecture on circadian rhythms. Third, we will determine the mechanisms that govern the spatiotemporal localization of cytosolic clock mRNAs and proteins to understand the organizing principles of cytoplasmic clock complexes. These studies have the potential to not only transform our understanding of how cells keep time at the molecular level in intact organisms, but will also provide new insights into important, overarching biological questions relevant to gene regulation in many contexts, including learning and memory, development, and disease. Using insights from this research our long-term goal is to engineer novel therapeutic approaches for the treatment of diseases associated with dysregulated clocks.
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