Developmental Biology We are studying the development of the intestine in the small free-living nematode worm Caenorhabditis elegans. The worm intestine develops as a simple clone of cells, entirely deriving from a single cell in the eight-cell embryo. We mainly focus on the transcription factor network that drives development of the intestine. From our work and that of others, we now know all the core transcription factors that control intestinal genes, from specification to differentiation, and they all are "GATA factors" similar to the factors that are central to the development of the human intestine. We are now trying to figure out how these factors actually work, i.e. to define the molecular and thermodynamic basis of developmental specificity. Does all the specificity reside in the DNA binding domain? And if so, how much does the binding free energy to an intestinal gene differ from the binding free energy to a gene expressed in a different lineage, e.g. the hypodermis (skin)? Are there other protein domains associated with endoderm specification and/or differentiation? Moreover, there must be dozens (perhaps many dozens) of additional factors that contribute to the expression of intestine specific genes besides the core GATA factors. We are trying to identify these other "chromatin" factors, using both biochemistry and classical genetic screens; in other words, we are trying to identify the regulators of the regulators. Our results should help us to understand the development of all organisms, including humans.
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