Abstract
The human population can be divided in two main groups based on their intestinal expression of lactase as adult individuals. Lactase persistent individuals express lactase throughout their lifespan, whereas lactase non-persistent individuals lose their lactase expression between the ages of 2-10 years. Lactase non-persistence is often associated with an inability to efficiently digest lactose, resulting in lactose intolerance. The lactase persistent phenotype is frequently found among northern Europeans and their descendants, but is also found among some African and Arabic populations (e.g., Tuareg, Fulbe, Beja, and Bedouin people).
The aim of this project is to investigate the molecular mechanisms behind the spatial and temporal expression of LPH. The human and the pig lactase promoter have therefore been cloned and functionally analyzed in order to understand the mechanisms behind lactase persistence and non-persistence, but also to elucidate the fundamental mechanisms behind the strict cell-specific expression of lactase in the mature enterocyte of the small intestine. Several key gene regulatory factors (Cdx-2, HNF1a, Fox's, HNF4a, Oct-1 and GATA-factors) important for intestinal expression have been identified, and this has fostered a detailed insight into how gene regulatory elements can be combined in promoters in order to direct intestinal-specific expression.
By studying the functional importance of a single nucleotide polymorphism that is tightly associated with lactase persistence/non-persistence, it was found that Oct-1 binds strongly to the lactase persistent variant of the SNP. The binding of Oct-1 is associated with strong stimulating gene-regulatory activity. The strong Oct-1 binding can be the key event that prevents the decline of lactase during childhood, resulting in the lactase persistent phenotype. A possible explanation for the lactase persistent phenotype is that the binding of Oct-1 compensates for a lower level of intestinal transcription factors after the weaning period. The lower expression of transcription factors after weaning may result in an insufficient activation of the lactase gene during differentiation of the enterocyte.
The aim of this project is to investigate the molecular mechanisms behind the spatial and temporal expression of LPH. The human and the pig lactase promoter have therefore been cloned and functionally analyzed in order to understand the mechanisms behind lactase persistence and non-persistence, but also to elucidate the fundamental mechanisms behind the strict cell-specific expression of lactase in the mature enterocyte of the small intestine. Several key gene regulatory factors (Cdx-2, HNF1a, Fox's, HNF4a, Oct-1 and GATA-factors) important for intestinal expression have been identified, and this has fostered a detailed insight into how gene regulatory elements can be combined in promoters in order to direct intestinal-specific expression.
By studying the functional importance of a single nucleotide polymorphism that is tightly associated with lactase persistence/non-persistence, it was found that Oct-1 binds strongly to the lactase persistent variant of the SNP. The binding of Oct-1 is associated with strong stimulating gene-regulatory activity. The strong Oct-1 binding can be the key event that prevents the decline of lactase during childhood, resulting in the lactase persistent phenotype. A possible explanation for the lactase persistent phenotype is that the binding of Oct-1 compensates for a lower level of intestinal transcription factors after the weaning period. The lower expression of transcription factors after weaning may result in an insufficient activation of the lactase gene during differentiation of the enterocyte.
| Original language | English |
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| Number of pages | 32 |
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| ISBN (Print) | 978-87-992467-0-0 |
| Publication status | Published - 2008 |