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Human Molecular Genetics Advance Access published online on November 21, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi418
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 12, 2005
Revised November 1, 2005
Accepted November 1, 2005

Article

THE T-13910 DNA VARIANT ASSOCIATED WITH LACTASE PERSISTENCE INTERACTS WITH OCT-1 AND STIMULATES LACTASE PROMOTER ACTIVITY IN VITRO

Rikke H. Lewinsky 1, Tine G.K. Jensen 1, Jette Møller 1, Allan Stensballe 2, Jørgen Olsen 1, and Jesper T. Troelsen 1 *

1 Department of Medical Biochemistry and Genetics, Building 6.4.24. Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
2 Department of Biochemistry & Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark

* To whom correspondence should be addressed.
Jesper T. Troelsen, E-mail: troelsen{at}imbg.ku.dk


  Abstract

Two phenotypes exist in the human population with regard to expression of lactase in adults. Lactase non-persistence (adult-type hypolactasia, lactose intolerance) is characterized by a decline in the expression of lactase phlorizin hydrolase 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 -13910 upstream the lactase gene. A nuclear factor binds more strongly to the T-13910 variant associated with lactase persistence than the C-13910 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-13910 variant. Supershift analyses show that Oct-1 binds directly to the T-13910 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-13910 variant/LPH promoter constructs only when it is co-expressed with HNF1{alpha}. Binding sites for other intestinal transcription factors (GATA-6, HNF4{alpha}, Fox and Cdx-2) were identified in the region of the -13910 T/C polymorphism. Three of these sites are required for the enhancer activity of the 13910-region. The data suggest that the binding of Oct-1 to the T-13910 variant directs increased lactase promoter activity and this might provide an explanation for the lactase persistence phenotype in the human population.


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