title: The Zinc Concentration in the Diet and the Length of the Feeding Period Affect the Methylation Status of the ZIP4 Zinc Transporter Gene in Piglets.
abstract: High doses of zinc oxide are commonly used in weaned pig diets to improve performance and health. Recent reports show that this may also lead to an imbalanced zinc homeostasis in the animal. For a better understanding of the regulatory mechanisms of different zinc intakes, we performed a feeding experiment to assess potential epigenetic regulation of the ZIP4 gene expression via DNA methylation in the small intestine of piglets. Fifty-four piglets were fed diets with 57 (LZn), 164 (NZn) or 2,425 (HZn) mg Zn/kg feed for one or four weeks. The ZIP4 expression data provided significant evidence for counter-regulation of zinc absorption with higher dietary zinc concentrations. The CpG +735 in the second exon had a 56% higher methylation in the HZn group compared to the others after one week of feeding (8.0·10-4 < p < 0.035); the methylation of this CpG was strongly negatively associated with the expression of the long ZIP4 transcripts (p < 0.007). In the LZn and NZn diets, the expression of the long ZIP4 transcripts were lower after four vs. one week of feeding (2.9·10-4 < p < 0.017). The strongest switch leading to high DNA methylation in nearly all analysed regions was dependent on feeding duration or age in all diet groups (3.7·10-10 < p < 0.099). The data suggest that DNA methylation serves as a fine-tuning mechanism of ZIP4 gene regulation to maintain zinc homeostasis. Methylation of the ZIP4 gene may play a minor role in the response to very high dietary zinc concentration, but may affect binding of alternate zinc-responsive transcription factors.
authors.affiliation: Breeding Biology and Molecular Genetics, Albrecht Daniel Thaer-Institute of Agri- and Horticulture, Faculty of Life Sciences, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Karweina
authors.affiliation: Breeding Biology and Molecular Genetics, Albrecht Daniel Thaer-Institute of Agri- and Horticulture, Faculty of Life Sciences, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kreuzer-Redmer
authors.affiliation: Breeding Biology and Molecular Genetics, Albrecht Daniel Thaer-Institute of Agri- and Horticulture, Faculty of Life Sciences, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Müller
authors.affiliation: Breeding Biology and Molecular Genetics, Albrecht Daniel Thaer-Institute of Agri- and Horticulture, Faculty of Life Sciences, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Franken
authors.affiliation: Institute of Animal Nutrition, Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Pieper
authors.affiliation: Epiontis GmbH, Berlin, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Baron
authors.affiliation: Epiontis GmbH, Berlin, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Olek
authors.affiliation: Institute of Animal Nutrition, Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Zentek
authors.affiliation: Breeding Biology and Molecular Genetics, Albrecht Daniel Thaer-Institute of Agri- and Horticulture, Faculty of Life Sciences, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Gudrun A
authors.initials: GA
authors.lastname: Brockmann
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004032:Diet; D004848:Epithelium / Q000378:metabolism; D005247:Feeding Behavior; D007583:Jejunum / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034421:Sus scrofa / Q000235:genetics*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015032:Zinc / Q000032:analysis* / Q000494:pharmacology
chemical_list: D027682:Cation Transport Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D015032:Zinc