Regulatory Circuitry Laboratory
Previous and current research
In general, we take an integrative approach, combining genome-wide transcription factor binding, gene expression perturbation using genetic manipulations, comparative genomics, and physiological approaches to understand on a systems-wide basis how a tissue is defined. To date, our work has:
- revealed the core circuitry of human hepatocytes and pancreatic islets,
- begun assessing how small collections of transcriptional regulators can dictate cellular biology, and
- preliminarily revealed the connections that exist between miRNA programs and transcription factor binding events.
Future projects
- Mapping regulatory circuitry: Ongoing projects in my laboratory use chromatin immunoprecipitation combined with deep sequencing to identify the complete set of transcription factor binding events for tissue-specific transcriptional regulators. Global knowledge of these binding events inform corresponding gene expression studies to reveal mechanistic insight into how directly-bound genes are controlled, and can serve to nucleate systems-wide models of transcriptional regulation.
- miRNA functional genomics: One practical output of these studies is the identification of candidate miRNAs which may be involved in tissue-specific transcriptional regulation. Because of their recent discovery, little is known about the function and downstream program of miRNAs. Forced expression of these miRNAs in stem cells or repression in their native tissues can reveal the genes miRNAs control.
- Conservation of master regulator targeting through evolution: Recent results suggest that few transcription factor-DNA interactions appear to be evolutionarily maintained, yet most evidence suggests that the gene expression programs of particular tissues are highly conserved. My laboratory is exploring the regulatory mechanisms that afford specific transcriptional programs resistance to evolutionary drift, despite surprisingly large changes in the binding of regulators.
