415C Biochemistry Additition
- Ph.D., Northwestern University
- Research Interests
- Studying the regulation of gene expression at the interface of chemistry, biology and genomics
- Research Fields
- Gene Expression, Genomics
The information required to produce a complex organism is encoded within its genome. A lens cell of the eye and an insulin-producing pancreatic cell contain identical genomic information yet access only a subset of that information. Thus, regulated expression of specific genes, in response to various cues, is what instructs cells to adopt defined fates in an organism. Inappropriate expression of genes can give rise to diseases, including cancer and diabetes. The broad goals of the lab are to understand the mechanistic events that culminate in the expression of specific genes, and to develop artificial transcription factors capable of regulating the expression of targeted genes. In a multidisciplinary effort, we utilize chemical, biological, biophysical, and genomic tools to address these goals.
Enzymes that modify transcription factors and the machinery Several enzymes — protein kinases, acetyl-transferases, ubiquitin-ligases — associate with the eukaryotic RNA polymerase II and influence its function. One such enzyme, a cyclin-dependent kinase, Cdk8/Srb10, plays both positive as well as negative roles in gene expression. We are using biochemical and genomic/proteomic tools to understand how Cdk8/Srb10 mediates these orthogonal roles.
Designer Transcription Regulators
Artificial transcription factors that can be designed to regulate a specific gene of interest offer a powerful tool to dissect transcriptional cascades that determine cell-fate. Such regulators could potentially develop into a new class of `transcription-based? therapeutics. In collaboration with Dr. Peter Dervan?s laboratory at Caltech, we are generating small molecule regulators that are capable of binding to specific DNA sequences and regulating the expression of proximal genes (see figures). These regulators function robustly in vitro and our current efforts are focused on targeting specific promoters in living organisms.
Dissecting Genome-wide transcriptional cascades
The Acute Promyelocytic Leukemia cell line, NB4, can differentiate into granulocytes when subjected to certain chemical stimuli. We are examining genome-wide expression patterns to determine if each of these chemicals reprogram a common set of transcriptional circuits which then suffice to induce differentiation (thereby remission from leukemia). In the future, we intend to test the ability of designer transcriptional regulators to stimulate specific transcriptional circuits and thus to identify the minimal set of circuits required to trigger differentiation in this as well as in other systems.
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