Human Molecular Genetics Advance Access originally published online on November 21, 2005
Human Molecular Genetics 2005 14(24):3945-3953; doi:10.1093/hmg/ddi418
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T–13910 DNA variant associated with lactase persistence interacts with Oct-1 and stimulates lactase promoter activity in vitro
1Department of Medical Biochemistry and Genetics, Panum Institute, University of Copenhagen, Building 6.4., Blegdamsvej 3, DK-2200 Copenhagen N, Denmark and 2Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark
* To whom correspondence should be addressed. Tel: +45 35327796; Fax: +45 35367980; Email: troelsen{at}imbg.ku.dk
Received September 12, 2005; Accepted November 1, 2005
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 HNF1
. Binding sites for other intestinal transcription factors (GATA-6, HNF4, 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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