GH plays a pivotal role in physiology, and is essential for normal somatic growth, tissue regeneration and repair, and intermediary metabolism. Many of the biological effects of GH are mediated by insulin- like growth factor I (IGF-I), a conserved secreted protein whose expression is potently induced by GH by activation of IGF-I gene transcription. As evidenced by linkage of GH and IGF-I with development of several cancers, and by their collective negative impact on aging, aberrant expression of IGF-I by GH may have deleterious pathogenic consequences, implying that its production must be tightly regulated to maintain homeostasis. The focus of this application will be on mechanisms by which GH controls IGF-I gene expression via the transcription factor Stat5b. Our studies will test the provocative hypothesis that IGF-I is fundamentally different from other GH-Stat5b target genes, and that multiple dispersed Stat5b-binding transcriptional enhancers, and other potentially inhibitory elements, are key agents in a complex regulatory program necessary to control expression of a potent growth factor with both positive and negative biological effects. The following two Specific Aims will test this idea: 1. To identify and characterize the chromosomal enhancers and repressors responsible for GH- and Stat5b-regulated Igf1 gene transcription. The major hypothesis to be tested is that discrete GH- activated enhancers with distinct functional properties interact with individual Igf1 gene promoters and are responsible collectively for mediating the acute transcriptional response to GH. A corollary hypothesis is that some GH-regulated elements in Igf1 chromatin are not transcriptional enhancers, but rather are putative negative regulators, and interfere with Igf1 promoter function in the absence of GH or sequester GH-stimulated Stat5b from positive sites. 2. To define the roles of GH and Stat5b in regulating chromatin plasticity of the Igf1 gene. The major hypothesis to be tested is that sustained GH-mediated signaling is required to establish an open chromatin environment at the Igf1 promoters, but that Stat5b is dispensable. A corollary hypothesis is that Stat5b is responsible for the acute chromatin modifications necessary for rapid induction of Igf1 gene transcription by GH. Proposed research has the potential impact to establish a new paradigm about mechanisms of GH action to regulate IGF-I gene expression, and to lead to new physiologically significant insights about how GH-mediated signaling controls epigenetic pathways, chromatin plasticity, and gene regulation.
GH actions are essential for normal somatic growth, for tissue maintenance and repair, and for normal intermediary metabolism in humans and other species, and are primarily mediated by IGF-I, a conserved secreted protein whose expression is induced by GH. The GH - IGF-I pathway also has been implicated in cancer development and in the negative aspects of aging, implying that its aberrant regulation has deleterious pathogenic consequences, and that its activity must be constrained at least in the adult to maintain homeostasis. The focus of this application is on the mechanisms by which GH regulates IGF-I gene expression through the conserved transcription factor, Stat5b, and is part of a longer-term goal to define how GH actions control epigenetic pathways and how chromatin modifications can potently regulate Stat5b functions in physiologically meaningful ways.
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