Interactions between drug response and gene regulation are bidirectional, strong, and often poorly understood. Drugs targeting ligandable transcription factors or chromatin modifying enzymes, for example, exert their effects directly, whereas drugs targeting cytoplasmic signaling pathways, cellular receptors, and even diverse cell types in the disease microenvironment impact gene regulation through indirect means. We are combining state-of-the-art experimental and computational approaches to define how key drugs used in oncology, inflammatory diseases, neurology and genetic diseases impact gene regulation in disease states. The results of these studies will help us better understand and treat disease.
The glucocorticoid receptor (GR) is a hormone-inducible transcription factor involved in metabolic and inflammatory gene expression that can be modulated with glucocorticoids, an important class of pharmaceuticals. We are defining the impact of glucocorticoids on genome structure and gene expression, in the process deriving fundamental insights into the complex logic of gene regulation. Funding provided by NIH/NHGRI
Cancer cell signaling states, encoded in part through gene regulation, control the sensitivity of tumors to drug therapies. Using large-scale gain- and loss-of-function screening and associated analysis, we have defined the landscape of signaling events that control the sensitivities of tumors to diverse targeted therapies. In the process, we have defined new resistance mechanisms, unveiled improved therapeutic strategies, and directly motivated new clinical trials. Funding provided by NIH/NCI and DOD