Human genomes are regulated by a complex network of protein interactions, where intrinsically disordered regions within transcription factors interact with well-folded domains in chromatin regulators, co-activators, and co-repressors to modulate RNA Polymerase II activity. However, the vast majority of these interactions are unknown. We are developing new high-throughput approaches for systematically mapping these interaction networks across cell types to uncover general principles of transcription factor-mediated gene regulation.

For decades, transcription factor activation domains have been considered as a monolith, from as far back as Paul Sigler's description of activation domains as 'negative noodles.' Recent work, however, has demonstrated that although activation domains are largely disordered, they leverage distinct physical mechanisms to enable highly specific recognition of particular co-activators. We use a high-throughput microfluidic technology we recently developed to quantitively measure the strength and timing of hundreds of direct protein-protein interactions to answer how disordered proteins recognize their partners.

Signaling molecules, such as hormones, growth factors, and other extracellular signals, bind to receptors on the cell surface, and initiate intracellular signaling cascades that ultimately lead to the activation or repression of specific genes. Transcriptional proteins are crucial in interpreting these signals and regulating gene expression in response. We are developing new high-throughput assays to systematically identify ligand-binding domains to discover proteins that act as both signal receivers and regulators of gene expression and to find potential new drug targets.