Eukaryotic organisms employ a variety of important, but poorly understood mechanisms to control the expression of their genes. An understanding of these mechanisms is an important issue since regulation of gene expression plays a pivotal role in the development and differentiation of functionally distinct cell types in a precise spatial manner. In addition, regulation of transcription reflects the ability of cells to respond to extracellular signals and environmental stress. The long term objectives of this research proposal are to understand the molecular mechanisms of inducible gene expression in higher eukaryotes using the interferon-beta (IFN-beta) gene as a model system. The IFN- beta gene is ordinarily tightly repressed, but is expressed at high levels when cells are infected with viruses or treated with double stranded RNA. Previous studies revealed a key role for the High Mobility Group protein HMG I(Y) in virus induction of the IFN-beta gene. HMG I(Y) is not a transcriptional activator on its own but functions in concert with other transcription factors. The highly specific activation of the IFN-beta gene in response to virus infection requires the assembly of a higher order nucleoprotein transcription enhancer complex, the enhanceosome. HMG I functions by promoting the assembly of the enhanceosome by mediating protein-DNA and protein-protein interactions. The overall goals of this proposal are to elucidate the molecular mechanisms by which HMG I(Y) promotes the assembly of the enhanceosome and how the enhanceosome stimulates transcription synergistically. First, a detailed structural and functional characterization of the HMG I(Y) proteins will be carried out to identify domains involved in DNA binding, protein-protein interactions and regions required for the assembly and the function of the IFN-beta enhanceosome. Second, in vivo assays and in vitro transcription systems will be used to determine the mechanisms by which the components of the IFN-beta gene enhanceosome function synergistically in the activation of transcription. If successful, the proposed experiments will provide significant new information regarding the structure and function of transcriptional regulatory proteins and sequences, as well as the mechanisms involved in signal transduction.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Biology Study Section (MBY)
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Tompkins, Laurie
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Columbia University (N.Y.)
Schools of Medicine
New York
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Falvo, James V; Lin, Charles H; Tsytsykova, Alla V et al. (2008) A dimer-specific function of the transcription factor NFATp. Proc Natl Acad Sci U S A 105:19637-42
Lomvardas, Stavros; Thanos, Dimitris (2002) Modifying gene expression programs by altering core promoter chromatin architecture. Cell 110:261-71
Agalioti, Theodora; Chen, Guoying; Thanos, Dimitris (2002) Deciphering the transcriptional histone acetylation code for a human gene. Cell 111:381-92
Lomvardas, S; Thanos, D (2001) Nucleosome sliding via TBP DNA binding in vivo. Cell 106:685-96
Munshi, N; Agalioti, T; Lomvardas, S et al. (2001) Coordination of a transcriptional switch by HMGI(Y) acetylation. Science 293:1133-6
Falvo, J V; Uglialoro, A M; Brinkman, B M et al. (2000) Stimulus-specific assembly of enhancer complexes on the tumor necrosis factor alpha gene promoter. Mol Cell Biol 20:2239-47
Agalioti, T; Lomvardas, S; Parekh, B et al. (2000) Ordered recruitment of chromatin modifying and general transcription factors to the IFN-beta promoter. Cell 103:667-78
Senger, K; Merika, M; Agalioti, T et al. (2000) Gene repression by coactivator repulsion. Mol Cell 6:931-7
Yie, J; Merika, M; Munshi, N et al. (1999) The role of HMG I(Y) in the assembly and function of the IFN-beta enhanceosome. EMBO J 18:3074-89
Munshi, N; Yie, Y; Merika, M et al. (1999) The IFN-beta enhancer: a paradigm for understanding activation and repression of inducible gene expression. Cold Spring Harb Symp Quant Biol 64:149-59

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