title: T-13910 DNA variant associated with lactase persistence interacts with Oct-1 and stimulates lactase promoter activity in vitro.
abstract: Two phenotypes exist in the human population with regard to expression of lactase in adults. Lactase non-persistence (adult-type hypolactasia and lactose intolerance) is characterized by a decline in the expression of lactase-phlorizin hydrolase (LPH) after weaning. In contrast, lactase-persistent individuals have a high LPH throughout their lifespan. Lactase persistence and non-persistence are associated with a T/C polymorphism at position -13,910 upstream the lactase gene. A nuclear factor binds more strongly to the T-13,910 variant associated with lactase persistence than the C-13,910 variant associated with lactase non-persistence. Oct-1 and glyceraldehyde-3-phosphate dehydrogenase were co-purified by DNA affinity purification using the sequence of the T-13,910 variant. Supershift analyses show that Oct-1 binds directly to the T-13,910 variant, and we suggest that GAPDH is co-purified due to interactions with Oct-1. Expression of Oct-1 stimulates reporter gene expression from the T and the C-13,910 variant/LPH promoter constructs only when it is co-expressed with HNF1alpha. Binding sites for other intestinal transcription factors (GATA-6, HNF4alpha, Fox and Cdx-2) were identified in the region of the -13,910 T/C polymorphism. Three of these sites are required for the enhancer activity of the -13,910 region. The data suggest that the binding of Oct-1 to the T-13,910 variant directs increased lactase promoter activity and this might provide an explanation for the lactase persistence phenotype in the human population.
authors.affiliation: Department of Medical Biochemistry and Genetics, Panum Institute, University of Copenhagen, Denmark.
authors.forename: Rikke H
authors.initials: RH
authors.lastname: Lewinsky
authors.forename: Tine G K
authors.initials: TG
authors.lastname: Jensen
authors.forename: Jette
authors.initials: J
authors.lastname: Møller
authors.forename: Allan
authors.initials: A
authors.lastname: Stensballe
authors.forename: Jørgen
authors.initials: J
authors.lastname: Olsen
authors.forename: Jesper T
authors.initials: JT
authors.lastname: Troelsen
mesh_terms: D001665:Binding Sites; D004742:Enhancer Elements, Genetic; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D043322:Lactase / Q000235:genetics* / Q000378:metabolism; D010694:Lactase-Phlorizin Hydrolase / Q000235:genetics / Q000378:metabolism; D007787:Lactose Intolerance / Q000235:genetics; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D050811:Octamer Transcription Factor-1; D014157:Transcription Factors; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D043322:Lactase; D010694:Lactase-Phlorizin Hydrolase