Professor in Developmental Biology; Pediatrics
Cincinnati Children's Hospital Medical Center
Title: Mechanisms of Homeodomain Transcription Factor Specificity
Abstract: The goal of my research program is to determine how homeodomain transcription factors that bind highly similar DNA sequences in vitro specify different developmental outcomes. Homeodomain genes constitute one of the largest groups of transcription factors in humans with over 200 family members that regulate a wide variety of processes including anterior-posterior patterning, organogenesis, and cell fate specification. Over 100 homeodomain genes encode disease-associated variants that impact numerous organs and tissues. Unfortunately, the identification of disease variants has greatly outpaced our understanding of their impact as hundreds of homeodomain missense alleles have been classified as variants of unknown significance. These findings raise three questions: (1) How do homeodomain proteins with highly similar DNA binding domains increase their DNA binding specificity to accurately regulate target genes? (2) How do the hundreds of missense variants associated with disease alter homeodomain function? (3) Once bound to DNA, how do homeodomain factors activate and repress target genes and what role does the type of binding site play in transcriptional outcomes? To address these questions, I work with an interdisciplinary research team that has developed a combined computational and experimental approach to discover that subsets of homeodomain factors form cooperative complexes on composite DNA sites with distinct site spacing and orientation requirements. In this presentation, I will discuss our recent findings on how homeodomain factors form cooperative transcription factor complexes and how disease associated variants that disrupt these complexes alter homeodomain function and dysregulate target gene expression.
Hosts: Oliver Hobert & Richard Mann
