Project Abstract Title: Metabolic and epigenetic drivers of stem cells in obesity and cancer PI: Miyeko Mana Our understanding of the relationship between diet, stem cells, and cancer is central to the prevention and treatment of this disease. With rising levels of obesity and the associated risk of cancer there is greater need to understand mechanisms by which diet influences tissue-specific stem cells that lead to oncogenic transformation. We have shown that a pro-obesity high-fat diet (HFD) increases stem cell number and niche independent growth in the mammalian intestine. We demonstrated that a HFD promotes stem cell self-renewal and tumorigenesis through the activation of a robust peroxisome proliferator-activated receptor delta (PPAR-δ) signature. Importantly, we showed these properties were bestowed upon the progenitor population thereby expanding the pool of cells capable of malignant growth. Our preliminary results indicate that multiple members of the PPAR family are required to establish the HFD phenotype in intestinal stem cells, and that PPAR redundancy signals the importance of downstream effectors. The biochemical and molecular underpinnings of the HFD will emerge through identification of the mechanistic steps that alter basic metabolism and epigenetic maintenance of the HFD transcriptional state. Our overall hypothesis is that a HFD markedly influences the metabolism and the stability of a PPAR transcriptional program that impact intestinal stem cells, tumor initiation and progression. We will test the premise that (Aim1) a HFD or agonist-activated PPAR establishes a state of dependency on the metabolic fatty acid oxidation program, and (Aim2) a HFD induces a stable transcriptional state by perturbing the chromatin landscape through chronic PPAR activity.