RESEARCH PROJECTS
Twenty-four hour rhythms in our physical and ecological environment present a challenge to the maintenance of physiological homeostasis. Circadian clocks enable organisms from bacteria to humans to predict and prepare for these daily fluctuations and enhance survival and overall health. Circadian rhythms play important roles in many aspects of mammalian physiology including glucose, drug, and tumor metabolism. Circadian disruption, such as that caused by shift work, increases the risk of many pathologies, including metabolic disease and cancer. We are dedicated to understanding the molecular mechanisms underlying these phenomena.
HOW DOES CIRCADIAN DISRUPTION INCREASE CANCER RISK?
Epidemiological studies have shown that chronic circadian disruption, such as that caused by shift work, leads to a small but significant increase in cancer risk. Furthermore, tumor formation in several mouse models of cancer is exacerbated by exposure to conditions that mimic rotating shift work in the laboratory (chronic jet lag).
We demonstrated that mice harboring Kras-driven lung adenocarcinoma develop 68% more tumors when they are exposed to chronic jet lag and that genes activated by the heat shock response transcription factor HSF1 are elevated in the lungs and tumors of those mice. Other recent studies have indicated that circadian rhythms modulate the ability of immune cells to impair tumor growth. We are using genetically engineered mouse models and single cell sequencing approaches to further investigate the contributions of these and other phenomena to increased tumorigenesis in response to circadian disruption.
CIRCADIAN REGULATION OF HIFs
In mammals, circadian clocks comprise a transcription-translation feedback loop, centered around a heterodimeric transcription factor complex containing CLOCK and BMAL1. CLOCK and BMAL1 are bHLH-PAS transcription factors closely related to ARNT and to HIF alpha subunits. At the time of its initial characterization, BMAL1 was found to be dispensable for developmental processes in which HIFs are key players and was therefore considered not to be a relevant partner for HIF alpha subunits. This impression was reinforced when X-ray crystal structures described divergent quaternary arrangements of the bHLH and PAS domain interfaces for CLOCK-BMAL1 and for HIFα-ARNT complexes. However, we and others have found that BMAL1 promotes HIF1α-dependent hypoxic responses. These findings motivate us to reconsider the possible physiological relevance of diverse bHLH-PAS heterodimer pairings. We are particularly interested in the potential for BMAL1 to partner with HIF2α, which is a key driver in clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer.
CIRCADIAN RHYTHMS AND EXERCISE
Regular exercise is an important component of a healthy lifestyle. Over the last 20 years, we and others have demonstrated that circadian clocks play a major role in synchronizing physiological processes with daily fluctuations in metabolic demand. For example, the liver circadian clock increases glucose production to compensate for the lack of dietary sugar intake during sleep. Recently, several groups have demonstrated that circadian rhythms influence both the health benefits of exercise and maximum exercise capacities.
We have found that circadian clocks in muscles alter the types of metabolites that are used for energy production during exercise at different times of the day. Furthermore, we demonstrated that the circadian repressors CRY1 and CRY2 regulate transcription factors involved in exercise, including nuclear hormone receptors like PPAR∂ and hypoxia inducible factors (HIFs). Further, time of day profoundly impacts the response to exercise training. We are currently investigating the muscle-intrinsic roles of CRYs in these phenomena.
