Emergent Specificity in the Disordered Nuclear Landscape

For decades, the prevailing model for eukaryotic transcription factor (TF) specificity held that structured DNA-binding domains (DBDs) find targets by recognizing fixed sequence motifs. But this framework—rooted in structural biology, biochemistry, and genomics—has grown misaligned with evidence. Eukaryotic genomes contain vast numbers of potential sites for any TF, yet only a small fraction is occupied in cells. In this talk I confront the paradox of how TFs achieve specificity in a nucleus where sites are overabundant and underspecified. Using single-molecule microscopy to track protein interactions in their native context, Cas9 genome editing, and a system for visualizing locus-specific binding in tissue, I show that DBDs are not the sole—or even primary—determinants of TF specificity. Instead, they act within a higher-order regulatory organization where interactions between long, unstructured protein regions—notoriously difficult to measure—play a central and underappreciated role.

11:50 am- Snacks & Socializing
noon- Talk Begins