366-OR: Characterization of Gene Expression Networks That Are Oppositely Regulated by Human and Mouse Metabolic Disease Using a Humanized Mouse Model

Abstract

Mouse is the most widely used preclinical animal model yet the translational rate from mouse studies to therapies of human disease is dismal. To identify differentially expressed gene networks that underlie the distinct pathophysiological responses in human and mouse, we compared the patterns of gene regulation by nonalcoholic fatty liver disease (NAFLD) in human and mouse. As expected, we identified approximately 1,600 genes whose expressions are similarly regulated by NAFLD in human and mouse. Intriguingly, however, we also identified a similar number of genes that exhibit completely opposite regulation. Pathway analysis revealed that similarly regulated genes performed similar function in human and mouse whereas oppositely regulated genes perform very different function, despite the same set of genes were analyzed in either mouse or human. To determine if these oppositely regulated genes truly reflect differences in human and mouse liver biology, we analyzed gene expression in chimera mice in which human and mouse hepatocytes co-exist in the humanized liver and are exposed to identical in vivo metabolic milieu. Strikingly, we were able to recapitulate a sizable fraction of oppositely regulated genes in a fast/refeeding cycle. We further analyzed the promoter activities and RNA stability of regulated genes and found that promoter occupancy by RNA pol II and a HuR-dependent post-transcriptional mechanism both contribute to the divergent regulations. Our findings suggest that there are a core set of genes, despite their conserved molecular function, might be differentially regulated and contribute to distinct physiological outcomes in human and mouse. Thus our work provide a timely resource to understand the molecular basis for divergent metabolic responses in human and mouse liver and also highlight the areas of human liver biology where mouse is not a suitable model, and a human or humanized system is needed for translational studies. Disclosure H. Cao: None. Funding National Institutes of Health