TRANSCRIPTIONAL REGULATION OF ZINC HOMEOSTASIS

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 DESCRIPTION (provided by applicant): Zinc is an essential nutrient that profoundly affects human health, as zinc deficiency and excess both result in a broad spectrum of pathologies. Zinc plays many roles in biological systems, since zinc is essential for the function of many proteins, and zinc modulates signal transduction pathways. A detailed understanding of zinc trafficking and homeostasis is critical for the development of new approaches for manipulating zinc to promote human health. There are major gaps in the current understanding of zinc homeostasis in animals, since fundamental mechanisms used to take up, sense, and excrete zinc are not well understood. Our long- term goal is to elucidate how animals sense zinc levels and coordinate a response that promotes zinc homeostasis. This goal will be addressed by analyzing zinc-regulated transcription factors and target genes using mammalian cells and the genetically tractable model organism C. elegans. Understanding how a network of proteins controls zinc homeostasis in an animal is an important objective of medical research, since the information may lead to new therapeutic approaches for diseases caused by abnormal zinc biology. Our preliminary results have established the powerful C. elegans model system for studies of zinc biology by the development of culture conditions that permit manipulation of dietary zinc, the establishment of assays that measure zinc content and distribution, and the identification of mutations in genes that control zinc biology. These results support three innovative hypotheses. (1) The HZA enhancer mediates transcriptional activation of multiple genes in response to excess zinc. The nuclear receptor NHR-33 is regulated by high dietary zinc and binds the HZA enhancer to control target genes that mediate homeostasis. (2) The ZIP transporter Y54G9A.4 promotes zinc uptake and is regulated by low dietary zinc. (3) The LZA enhancer mediates transcriptional activation of multiple genes in response to zinc deficiency. To test these hypotheses, we propose three specific aims. Aim 1: Characterize the regulation and evolutionary conservation of nuclear receptors in mediating zinc homeostasis. Aim 2: Identify and functionally analyze target genes regulated by high dietary zinc. Aim 3: Analyze the function and regulation of the ZIP gene Y54G9A.4. Characterize the LZA enhancer that mediates transcriptional regulation in response to zinc deficiency, and identify protein factors that regulae this element. These experiments build on our accomplishments in the previous grant period that established the C. elegans model system for studies of zinc biology and generated innovative new hypotheses. This proposal will extend these discoveries to mammalian systems and exploit the powerful experimental advantages of C. elegans to elucidate how a network of genes regulates zinc homeostasis in a multicellular animal. Several prevalent human diseases such as Alzheimer's disease, stroke and cancer have been associated with abnormalities of zinc homeostasis, and the results of these studies may suggest new therapeutic strategies for addressing disorders of zinc toxicity.