Specification of Mammalian Cell Types

The main focus of the laboratory is to understand regulatory networks that specify different mammalian cell types. As a model system, we are studying the extracellular signals and genetic regulatory proteins that cause hepatocytes to be specified from the endoderm in mouse development. We address this problem several ways. First, we investigate signalling between cells derived from mouse endoderm and inductive mesenchyme, using either primary cultures of embryo tissue or virally transformed cell lines we created from embryo cell cultures. Second, we investigate transcription factors that control early hepatic development; the factors have been identified by their importance in maintaining the differentiated state of adult liver tissue, studies of nascent hepatic tissue in mouse embryos, or by sequence homology with factors causing endoderm differentiation in other organisms. Finally, we study how transcription factors modulate chromatin structure in the process of activating transcription. To this end, we use in vivo footprinting to monitor factor occupancy and map nucleosome positions in chromatin, and in vivo chromatin reconstitution systems to understand the mechanism of factor binding to nucleosomes and the formation of an active complex of regulatory proteins bound to DNA.

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