Developmental Biology Program
Molecular Cell Biology Program

We are interested in understanding how embryonic and embryonic stem (ES) cells regulate self-renewal, lineage commitment, and differentiation and are studying these questions in the context of vertebrate neural development. Stepwise transcriptional cascades convert pluripotent embryonic cells into neurons:  multipotent neural precursors form, commit to neuronal lineages, and then undergo cell cycle withdrawal and neuronal differentiation. We use both mouse ES cells and mouse and Xenopus embryos to study these processes.

A major focus of our work is on chromatin regulatory proteins, including the SWI-SNF and Polycomb complexes and the novel protein Geminin. These complexes critically regulate transcription to control self-renewal and differentiation in multiple cell contexts. They also regulate cell cycle progression and maintain genome integrity and their dysregulation is a pivotal aspect of multiple human malignancies.  Our current efforts include:

Transcriptional regulatory networks in neural development.  We are: 1. identifying direct targets and regulatory enhancers used by several key bHLH transcription factors to regulate neuronal commitment, 2. determining how neural precursor-specific gene expression is transcriptionally regulated in early embryos and ES cells, and 3. Using genomic and function-based screens to isolate novel regulators of neurogenesis.

Gem, SWI-SNF, and Polycomb interplay regulating transcription in embryonic and ES cells. We are defining how interactions between these complexes regulate transcription by defining direct transcriptional targets, composition of the protein complexes involved, and mechanisms of action at the chromatin level. We are also assessing how this is integrated with control of cell cycle progression and genome stability/euploidy, to determine how this occurs in normal cells and define its contributions to cancer progression.

---