Transcriptional Regulatory Circuitry in Development and Disease

We are interested in the regulatory circuitry that controls the gene expression programs in each of our cells. Since defects in transcriptional regulation can cause diabetes, cancer, hypertension, immune deficiencies and neurological disorders, improved understanding of this circuitry should lead to new insights into disease mechanisms and the development of new diagnostics and therapeutics.

Transcriptional regulatory circuitry consists of a specific population of protein and RNA regulators that work together to produce a gene expression program. The complete population of regulators involved in transcriptional regulatory circuitry has yet to be determined for any cell. However, for some cells, such as embryonic stem (ES) cells, key transcriptional and chromatin regulators have been identified. We can use this knowledge of key regulators to begin mapping the core regulatory circuitry of ES cells and other cell types.

We have developed a powerful method called genome-wide location analysis, or ChIP-on-Chip, which uses chromatin immunoprecipitation and DNA microarrays together with computational analysis to map the genomic sites bound by protein regulators in healthy and diseased cells. These maps reveal the location of transcriptional regulators, chromatin regulators, and histone modifications throughout the genome of a cell. This information, when coupled with gene expression data, allows us to deduce portions of the cell's transcriptional regulatory circuitry.