Regulation of homotypic and heterotypic interactions in transcription factors

Abstract

Fine-tuned regulation of transcription in cells is essential for proper differentiation, development, and signaling. Transcription factors (TFs) represent an important class of transcriptional regulators that recognize specific DNA sequences and contribute to changes in gene expression. TFs engage in various homotypic and heterotypic interactions with protein cofactors that provide opportunities for their regulation. Aberrant TF function is implicated in a wide range of diseases, but small molecule-mediated modulation of TFs remains a challenging task. Recent advances in chemically induced proximity (CIP) and targeted protein degradation (TPD), however, have highlighted novel ways to perturb TF function, stability, and localization. In this dissertation, I use structural, biochemical, and computational approaches to investigate homotypic interactions among the ZBTB family of TFs and drug-induced heterotypic interactions between the E3 ligase CRBN and ZF domain-containing TFs. Our results from the former study indicate that polymerization in ZBTB TFs enhances their transcriptional effector functions and presents opportunities for therapeutic modulation. Moreover, our latter study defines the landscape of ZF domain-containing TFs amenable to CRBN-focused TPD approaches. Taken together, this dissertation augments our understanding of how TF-mediated interactions and their regulation can be utilized for pharmacological benefit.