The Role of Cryptochromes in Circadian Regulation of Metabolism

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Project Summary / Abstract Circadian rhythms are pervasive among organisms, allowing them to anticipate and adapt to the predictable 24-hour day-night cycle. Their function is to temporally coordinate physiological processes, such as metabolism, within the organism. Consequently, the disruption of circadian rhythms leads to desynchronized internal clocks and complex metabolic disorders, such as diabetes. The mechanism of how the clock controls downstream metabolic pathways is not well-established. One of the central players in this relationship is the core clock gene Cryptochrome (Cry). CRY is necessary to maintain rhythmicity and determine period length, but it has also been implicated in diabetes and glucose tolerance. Until recently, CRY was thought to function only in the nucleus; our recent unanticipated findings indicate it also inhibits gluconeogenesis in the cytoplasm through its interaction with Gsα. In parallel, nuclear CRY also regulates gluconeogenesis, albeit through a completely different pathway. Together, this two-pronged approach allows CRY to fine-tune its regulation of glucose homeostasis; however, its presence in two subcellular locales has made it difficult to study its compartment-specific mechanisms. To overcome this challenge, we created two unique reagents that localize CRY to each region. Cytosolic CRY will be studied at the atomic and cellular level to identify its binding partners and how their interactions determine their biochemical functions. Nuclear CRY will be investigated on the genomic scale to uncover its interactions with other transcription factors in the enhancers of gluconeogenesis genes. Chromosome conformation capture techniques will enable us to model nucleus-wide hepatocyte-specific enhancer architecture. On the therapeutic front, we will characterize the mechanism of action of novel clock-modifying chemical compounds identified from our screens. These compounds have the potential to identify novel clock genes and to regulate metabolism, paving the way towards clinical translation. The use of these techniques to study how CRY controls gluconeogenesis will be a proof-of-concept for how the clock achieves precision in modulating a tissue-specific metabolic pathway. The success of these studies will significantly improve the understanding of the crosstalk between the biological clock and physiology or disease states, as well as provide a proof-of-concept model for applying cell-based findings in improving human health.