Genetics of Runt-Dependent Transcription

This project uses genetic approaches to investigate the biochemical mechanisms of transcriptional regulation by the Drosophila Runt transcription factor. Runt domain proteins comprise a small family of transcriptional regulators that have pivotal roles in regulating gene expression in diverse developmental pathways extending from segmentation in insect embryos to hematopoiesis and osteogenesis in mammals. These proteins function as either activators or repressors of transcription in a manner that depends on the specific target gene and the developmental context. This project takes advantage of the wealth of information available on Drosophila segmentation, as well as several genetic tools that are available in this system to investigate the mechanisms of activation and repression by Runt, the founding member of this family of transcriptional regulators. An ongoing genetic dissection of Runt's activity as a transcriptional repressor takes advantage of the lethality associated with the Runt-dependent repression of the segment-polarity gene engrailed (en). Other factors that cooperate with Runt are identified as suppressors of this lethality are then molecularly characterized for their specific roles in transcriptional repression. This project also uses similar genetic approaches to investigate the mechanism of Runt-dependent activation of fushi tarazi (ftz) a second key target in the Drosophila segmentation pathway. Molecular and biochemical approaches and structure function studies that use in vivo assays will be used to investigate interactions between Runt, Ftz-F1 and Lilliputian, and the relative roles of these three DNA-binding factors in ftz activation. This project will contribute to the understanding of the mechanisms of Runt-dependent transcriptional regulation and will provide insights on in vivo mechanisms for transcriptional regulation that are not so readily obtained in other systems. In addition, training opportunities for several students, from the high school to graduate school level, will be offered through this project.