Revealing the mechanisms behind adult-type hypolactasia by studies of the regulation of the lactase phlorizin hydrolase gene.

Jesper Thorvald Troelsen

Revealing the mechanisms behind adult-type hypolactasia by studies of the regulation of the lactase phlorizin hydrolase gene.

Jesper Thorvald Troelsen

Institut for Cellulær og Molekylær Medicin

Abstract

Den humane population kan opdeles i to hovedgrupper baseret på deres ekspression af laktase som voksne. Laktase persistente udtrykker laktase hele livet hvorimod hos laktase non-persistente falder laktase ekspression til et lavt niveau ved 2-10 års alderen. Laktase non-persistens medfører ofte at laktose ikke bliver fordøjet effektivt og hvilket medfører laktose intolerans.
   Den laktase persistente fænotype er især almindelig i Nordeuropa og hos udvandrere fra denne region, men den findes også hyppigt i nogle afrikanske og arabiske populationer, f.eks hos Tuareg, Fulbe, Beja-folkene og beduiner.
   Målet for forskningsprojektet har været at afdække de molekylære mekanismer bag LPH ekspression både rummeligt og udviklingsmæssigt. Menneskets og grisens laktase promotere blev derfor klonet og analyseret funktionelt for dels at undersøge mekanismerne bag laktase persistens og non-persistens, men også for at belyse de fundamentale mekanismer bag den celle-specifikke ekspression af laktase i tyndtarmens enterocytter. Flere centrale gen-regulatoriske faktorer (Cdx-2, HNF1a, Fox, HNF4a, GATA-faktorer) med betydning for tarm-ekspression er blevet identificeret. Dette har givet et detaljeret billede af hvordan gen-regulatoriske DNA sekvenser kombineres for at opnå tarm-specific ekspression.
   Ved at studere den funktionelle betydning af en single nucleotide polymorphism, som er tæt associeret til laktase persistens/non-persistens, har vi identificeret transkriptionsfaktoren Oct-1. Oct-1 binder kraftigt til den laktase persistente SNP variant og denne binding er associeret med en kraftig gen-stimulerende aktivitet. Denne kraftige Oct-1 binding kan være hovedårsagen til, at laktase genet hos laktase persistente ikke nedreguleres. Forklaringen kan være, at Oct-1 kompenserer for en generel nedregulering af tarm-specifikke transkriptionsfaktorer efter diegivningsperioden. Denne generelle nedregulering forårsager, at laktase genet hos laktase non-persistente ikke bliver aktiveret i de modne epitel-tarmceller, som det sker hos spædbørn. Tilstedeværelsen af Oct-1 binding sekvensen hos laktase persistente sørger for en øget rekruttering af transkriptionsfaktorer til laktase genet, hvilket medfører en aktivering af laktase genet hos de persistente trods den lavere ekspression af transkriptionsfaktorer efter diegivningsperioden.

Originalsprog	Engelsk

Antal sider	32
ISBN (Trykt)	978-87-992467-0-0
Status	Udgivet - 2008

Citationsformater

@phdthesis{4df28f10e17811ddb5fc000ea68e967b,

title = "Revealing the mechanisms behind adult-type hypolactasia by studies of the regulation of the lactase phlorizin hydrolase gene.",

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.",

author = "Troelsen, {Jesper Thorvald}",

year = "2008",

language = "English",

isbn = "978-87-992467-0-0",

}

TY - THES

T1 - Revealing the mechanisms behind adult-type hypolactasia by studies of the regulation of the lactase phlorizin hydrolase gene.

AU - Troelsen, Jesper Thorvald

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

M3 - Doctoral thesis

SN - 978-87-992467-0-0

BT - Revealing the mechanisms behind adult-type hypolactasia by studies of the regulation of the lactase phlorizin hydrolase gene.

ER -

Revealing the mechanisms behind adult-type hypolactasia by studies of the regulation of the lactase phlorizin hydrolase gene.

Abstract

Fingeraftryk

Citationsformater