Our laboratory studies molecular control of development and cell differentiation using self-renewing epithelia in the digestive tract as a model system.

The gastrointestinal tract is especially suited for molecular investigation of mechanisms that regulate lifelong stem cell self-renewal. Furthermore, because communication between endoderm (prospective epithelium) and its adjoining mesenchyme is crucial in organogenesis and homeostasis, the digestive tract is a useful model to study tissue-tissue interactions. The laboratory has identified novel regulators of cell differentiation, determined their functions in vivo, and advanced understanding of how chromatin and transcription factors interact to generate cell-specific transcriptional programs and tissue identity.

Surprisingly few pathways mediate signaling in mammalian development and differentiation, including Wnt, Hedgehog and Notch. We study how these ubiquitous pathways signal through tissue-restricted transcription factors to generate diverse and specific cell fates. We use whole-genome analysis of transcription factor binding and histone modifications in intestinal epithelial cells to determine how regulatory factors interact with one another and with chromatin to produce tissue-specific outcomes in normal and malignant epithelia. These approaches combine the power of modern genomics with sound experimental models to understand how cells and tissues transition between alternative fates.

An important goal of the laboratory is to understand how cellular relationships established in embryos are subverted in cancer. We especially seek to characterize processes that are active in development and silent in the normal adult tissue, but reactivated in tumors. Such processes shed light on developmental mechanisms relevant to tumorigenesis and reveal aspects of the disease that may be sensitive to novel therapies.