Eukaryotic Transcriptional Regulation

National Institute Of Environmental Health Sciences

Investigators

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Abstract

Our research program is divided into two different subject areas, both of which address molecular mechanisms integral to chronic human disease. One major focus area for the laboratory studies the transcription factor GATA3. This essential transcription factor is a frequent target of mutation in human breast cancer – approximately 10% of all breast cancer cases bear a mutation in this protein. Our studies of GATA3 follow two general strategies. First, we use cell culture and animal models to assess how cancer-specific mutation in GATA3 impacts its function in regulating transcription and cell identity. Second, we are engaged in mechanistic biochemical, structural and genomic experiments designed to understand how the protein engages chromatin and regulates genes. These basic studies will provide critical inputs to our study of how cancer-specific mutation impacts function, leading to human disease. The second major focus of our laboratory studies how consumption of excess calories leads to increased disease risk in a mouse model of diet-induced obesity. We find that mice fed a diet rich in energy, with the majority of calories derived from fat, become obese and their colon epithelial cells activate enhancers implicated in colon cancer progression. As obesity represents a principal disease risk for colorectal cancer development in humans, we interpret this data to suggest that environmental factors, such as diet, can influence disease risk in part through epigenetic alteration in target tissue. Current experiments in the lab are aimed at dissection of specific components of diet, interrogation of the role of the microbiome, assessing the contribution of systemic inflammation characteristic of the obese, and testing of disease risk using animal models of tumor development and/or progression.