Function and regulation of the ETS transcriptional repressor Tel-1/Yan

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DESCRIPTION (provided by applicant): The long-term objectives of this work are to elucidate how transcriptiona! circuitries operating downstream of conserved signaling networks mediate context-specific developmental responses. Because precisely orchestrated regulation of gene expression is fundamental to all biological processes, even slight imbalances can lead to serious defects and diseases. Our approach is to exploit the genetically tractable Drosophila system to uncover novel strategies of gene regulation, to dissect them in vivo at a molecular mechanistic level of detail, and then to confirm their conservation and relevance to mammalian systems. The goal of this proposal is to investigate the in vivo function and regulation of a conserved ETS family transcriptional repressor, referred to as Yan in Drosophila and Tel1 in humans. The proposal describes a multifaceted approach combining in vivo genetic, molecular, biochemical and genomic assays to address the hypothesis that homo- and heterotypic interactions mediated by the SAM domain of Tel1/Yan permit a complex association with chromatin that is essential for developmental gene regulation. The specific aims are to test the hypothesis that the ability of Yan to self-associate is required for its function as a transcriptional repressor in vivo, to investigate the mechanisms whereby regulated Yan polymerization allows it to spread into chromatin flanking a canonical high affinity binding site, and to explore the conservation of these regulatory strategies with respect to human Tel1. The results of these experiments will define a novel paradigm in transcriptional repression, in which dynamic polymerization of a gene specific transcriptional regulator can modulate expression of downstream target genes in response to changing signaling conditions. Because the signaling molecules we are studying have conserved functions in mammals, and because Tel1 is a frequent target of leukemia-associated chromosomal rearrangements, our findings will be directly applicable to understanding human development and disease. Given that the ability of Tel1 to self-associate is thought to provide a driving force toward malignant transformation in several common leukemias, the mechanistic discoveries emanating from these studies will provide an important foundation for developing novel therapeutic interventions to treat Tell-associated cancers in the future.