title: A modular system of DNA enhancer elements mediates tissue-specific activation of transcription by high dietary zinc in C. elegans.
abstract: Zinc is essential for biological systems, and aberrant zinc metabolism is implicated in a broad range of human diseases. To maintain homeostasis in response to fluctuating levels of dietary zinc, animals regulate gene expression; however, mechanisms that mediate the transcriptional response to fluctuating levels of zinc have not been fully defined. Here, we identified DNA enhancer elements that mediate intestine-specific transcriptional activation in response to high levels of dietary zinc in C. elegans. Using bioinformatics, we characterized an evolutionarily conserved enhancer element present in multiple zinc-inducible genes, the high zinc activation (HZA) element. The HZA was consistently adjacent to a GATA element that mediates expression in intestinal cells. Functional studies using transgenic animals demonstrated that this modular system of DNA enhancers mediates tissue-specific transcriptional activation in response to high levels of dietary zinc. We used this information to search the genome and successfully identified novel zinc-inducible genes. To characterize the mechanism of enhancer function, we demonstrated that the GATA transcription factor ELT-2 and the mediator subunit MDT-15 are necessary for zinc-responsive transcriptional activation. These findings define new mechanisms of zinc homeostasis and tissue-specific regulation of transcription.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Roh
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dimitrov
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Krupa
authors.initials: K
authors.lastname: Deshmukh
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Guoyan
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Warnhoff
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cabrera
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Tsai
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA kornfeld@wustl.edu.
authors.forename: Kerry
authors.initials: K
authors.lastname: Kornfeld
mesh_terms: D000818:Animals; D001483:Base Sequence; D002104:Cadmium / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D017124:Conserved Sequence; D018509:DNA, Helminth / Q000737:chemistry; D004742:Enhancer Elements, Genetic; D050980:GATA Transcription Factors / Q000378:metabolism; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D018509:DNA, Helminth; C094134:ELT-2 protein, C elegans; D050980:GATA Transcription Factors; C571065:MDT-15 protein, C elegans; D014157:Transcription Factors; D002104:Cadmium; D015032:Zinc