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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM080372-03
Application #
7637794
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Tompkins, Laurie
Project Start
2007-07-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$291,650
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Hope, C Matthew; Webber, Jemma L; Tokamov, Sherzod A et al. (2018) Tuned polymerization of the transcription factor Yan limits off-DNA sequestration to confer context-specific repression. Elife 7:
Webber, Jemma L; Zhang, Jie; Massey, Alex et al. (2018) Collaborative repressive action of the antagonistic ETS transcription factors Pointed and Yan fine-tunes gene expression to confer robustness in Drosophila. Development 145:
Boisclair Lachance, Jean-François; Webber, Jemma L; Hong, Lu et al. (2018) Cooperative recruitment of Yan via a high-affinity ETS supersite organizes repression to confer specificity and robustness to cardiac cell fate specification. Genes Dev 32:389-401
Hope, C Matthew; Rebay, Ilaria; Reinitz, John (2017) DNA Occupancy of Polymerizing Transcription Factors: A Chemical Model of the ETS Family Factor Yan. Biophys J 112:180-192
Peláez, Nicolás; Gavalda-Miralles, Arnau; Wang, Bao et al. (2015) Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation. Elife 4:
Boisclair Lachance, Jean-François; Peláez, Nicolás; Cassidy, Justin J et al. (2014) A comparative study of Pointed and Yan expression reveals new complexity to the transcriptional networks downstream of receptor tyrosine kinase signaling. Dev Biol 385:263-78
Webber, Jemma L; Rebay, Ilaria (2014) Long-range integration of repressive and patterning inputs. Cell Cycle 13:1653-4
Webber, Jemma L; Zhang, Jie; Mitchell-Dick, Aaron et al. (2013) 3D chromatin interactions organize Yan chromatin occupancy and repression at the even-skipped locus. Genes Dev 27:2293-8
Webber, Jemma L; Zhang, Jie; Cote, Lauren et al. (2013) The relationship between long-range chromatin occupancy and polymerization of the Drosophila ETS family transcriptional repressor Yan. Genetics 193:633-49
Zhang, Jie; Graham, Thomas G W; Vivekanand, Pavithra et al. (2010) Sterile alpha motif domain-mediated self-association plays an essential role in modulating the activity of the Drosophila ETS family transcriptional repressor Yan. Mol Cell Biol 30:1158-70

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