2021 New Investigator Grant
Zheng Kuang, Ph.D. Assistant Professor, Department of Biological Sciences, Carnegie Mellon University
Microbial regulation of sex-specific circadian rhythms in the mammalian gut
Abstract
Mammalian metabolism is regulated differently in males and females, which leads to different metabolic phenotypes and prevalence of metabolic diseases. For example, females tend to store more lipids than males and they are more sensitive to insulin. Consistently, obesity and diabetes are more prevalent in men than women. Emerging evidence shows that the intestinal microbiota, a community of microorganisms residing in our gut, makes important contributions to gender-dependent differences in metabolism; however, the molecular basis remains a mystery. We have recently found that the gut microbiota is required for daily oscillations of intestinal histone methylation in male mice but not females. The methylation mark regulates hundreds of genes implicated in nutrient absorption and metabolism. These observations suggest that the microbiota may exploit some sex-specific machinery in the intestine to program host circadian rhythms and couple host metabolic activities with the 24-hour day/night light cycle. This project will study how the gut microbiota regulates the sex-specific diurnal rhythms in the intestine, and how this affects nutrient uptake and energy homeostasis. We will use a combination of mouse genetics, genomics, chemistry and machine learning approaches to explore the role of a male-specific chromatin modifier in this microbial regulation of host metabolic rhythms. The findings will provide novel insights into how genetic and environmental factors come together in the gut to regulate the sexual dimorphism in metabolism and help develop new therapeutic strategies to protect against metabolic diseases by targeting the microbiota or intestinal histone methylation. In addition, this project will provide a valuable opportunity to engage and train undergraduate and graduate students and prepare them for future careers in biological and biomedical research.