Project 461757

We live in a 24-hour world where our daily activities are organized around the day-night cycle. Many of us wake up, eat our meals, go to work, and sleep at approximately the same time every day. Our internal organs behave in a similar fashion, changing their activities over the course of 24 hours. These daily, "circadian" rhythms in behaviour and physiology are driven by the rhythmic expression of a set of clock genes in cells throughout the body as well as in the brain, where the master clock, the suprachiasmatic nucleus (SCN), resides. As the central pacemaker, the SCN is responsible for keeping track of the time of day and conveying that information to peripheral tissues. When the timekeeping ability of the SCN is compromised, there can be serious health consequences, including sleep disturbances and increased risk of obesity, diabetes, high blood pressure, heart disease, breast and prostate cancer, major depression, and Alzheimer's disease. Therefore, to ensure that our circadian rhythms optimally support our physical and mental health, it is imperative that we understand how the SCN functions. The objective of this proposal is to investigate the role of histone variant proteins in timekeeping processes within the SCN. Changes in gene expression rely on the ability of histone variant proteins to either incorporate into or vacate specific sites in our genome. However, their involvement in mammalian clock gene expression and their impact on circadian rhythms have yet to be examined. To this end, we will determine the functional importance of the histone variants H2A.Z.1 and H2A.Z.2 in circadian timekeeping using mouse models where the respective genes have been "knocked out" in the SCN. Through our work, we will acquire new insights into how the SCN is regulated, knowledge that may be leveraged for the development of therapeutic and health-promoting strategies that target our circadian clock.