Understanding the molecular logic of regulatory strategies that control genome-wide patterns of transcriptional response to regulatory signals, development and human disease remains a key, unresolved issue. Under this Grant, we have investigated the integration of transcriptional programs by coactivators and corepressors and have established their role in regulated gene transcription by DNA binding transcription factors. Furthermore, we have established the critical role of specific corepressor complex components in cofactor exchange in ligand-dependent gene activation. We have investigated the effects of ligands on long-distance interactions in normal cells and as a component of tumor biology, including translocation events. Investigation of pituitary gland development as a model has permitted the in vivo characterization of new aspects of the Notch pathway and the role of Wnt pituitary/2-catenin POU domain interactions in cell type-specific gene activation events. In this competitive renewal, based on preliminary data obtained under this Grant, we will focus on the role of nuclear receptor-mediated transcriptional activation driven by specific response elements in a large number of DNA repeats resulting in novel small regulatory RNAs and ligand-regulated ncRNAs. We will develop and apply genome-wide location analysis 3-D interaction methods to explore new aspects of gene regulation and control of transcriptional activation programs aimed at identifying specific strategies of enhancers and regulation of subnuclear location events during development and in control of proliferation. We also propose a novel non-histone methylation strategy, which is critical for the movement of transcription units between the nuclear architecture regions that underlie growth control gene regulation. Our studies will link non-histone protein modifications, ncRNAs and nuclear architecture as an integrating strategy for regulated mammalian transcriptional programs.
The experiments proposed in this competitive renewal will provide novel insights into regulated patterns of gene transcription, focusing on new technologies to investigate the role of ligand-dependent induction of DNA repeats and gene enhancers in gene expression programs and in ncRNAs and nuclear architecture strategies critical for integrating gene transcriptional programs. The proposed studies have particular relevance in uncovering the molecular basis of growth control and nuclear receptor actions in normal and cancer cells. Understanding these new strategies underlying regulation of gene expression is likely to translate into new types of therapeutic modalities.
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