Functional characterization of an allergy-associated regulatory variant at the human IL13 locus

Persistent Link:
http://hdl.handle.net/10150/193656
Title:
Functional characterization of an allergy-associated regulatory variant at the human IL13 locus
Author:
Kiesler, Maria Olga Patricia
Issue Date:
2009
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
T helper type--2 (Th2) immunity orchestrates responses against extracellular pathogens under normal conditions and mediates pathogenic responses against innocuous substances when dysregulated, leading to allergic disease. Among the cytokines expressed by Th2 cells, interleukin (IL)--13 has emerged as a critical effector molecule in Th2 responses and common IL13 variants are associated with allergy--related phenotypes in populations of distinct ethnic background. IL13 expression in human T cells is paralleled by extensive IL13 locus remodeling, which results in the appearance of multiple DNase I hypersensitive (HS) sites. Among these, HS4 in the distal IL13 promoter is constitutively present in both naive and polarized Th2 cells, and spans a single nucleotide polymorphism, IL13--1512AC (rs1881457), which is common and strongly associated with total serum IgE levels. This dissertation combines in vitro and ex vivo approaches to characterize the role of HS4 in the regulation of IL13 gene expression and to provide novel insights into the mechanisms that underlie the association between IL13--1512AC and allergic disease.The results showed that HS4 acts as a novel cis--acting element that up--regulates IL13 transcription in activated Th2 cells. The enhancing activity of HS4 mapped within the 3' end of this element and was dependent on binding/recruitment of the transcription factors NF90 and NF45. Moreover, the IL13--1512C risk allele significantly enhanced HS4--dependent IL13 expression by creating a binding site for the transcription factor Oct--1. The increased expression of the --1512C allele was dependent on endogenous levels of Oct--1. Collectively, these results illustrate how a functional variant in an important regulatory element may modulate susceptibility to a common complex disease.
Type:
text; Electronic Dissertation
Keywords:
Allergy; IL13; Polymorphism; T cells; Transcriotional Regulation
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Genetics; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Vercelli, Donata

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleFunctional characterization of an allergy-associated regulatory variant at the human IL13 locusen_US
dc.creatorKiesler, Maria Olga Patriciaen_US
dc.contributor.authorKiesler, Maria Olga Patriciaen_US
dc.date.issued2009en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractT helper type--2 (Th2) immunity orchestrates responses against extracellular pathogens under normal conditions and mediates pathogenic responses against innocuous substances when dysregulated, leading to allergic disease. Among the cytokines expressed by Th2 cells, interleukin (IL)--13 has emerged as a critical effector molecule in Th2 responses and common IL13 variants are associated with allergy--related phenotypes in populations of distinct ethnic background. IL13 expression in human T cells is paralleled by extensive IL13 locus remodeling, which results in the appearance of multiple DNase I hypersensitive (HS) sites. Among these, HS4 in the distal IL13 promoter is constitutively present in both naive and polarized Th2 cells, and spans a single nucleotide polymorphism, IL13--1512AC (rs1881457), which is common and strongly associated with total serum IgE levels. This dissertation combines in vitro and ex vivo approaches to characterize the role of HS4 in the regulation of IL13 gene expression and to provide novel insights into the mechanisms that underlie the association between IL13--1512AC and allergic disease.The results showed that HS4 acts as a novel cis--acting element that up--regulates IL13 transcription in activated Th2 cells. The enhancing activity of HS4 mapped within the 3' end of this element and was dependent on binding/recruitment of the transcription factors NF90 and NF45. Moreover, the IL13--1512C risk allele significantly enhanced HS4--dependent IL13 expression by creating a binding site for the transcription factor Oct--1. The increased expression of the --1512C allele was dependent on endogenous levels of Oct--1. Collectively, these results illustrate how a functional variant in an important regulatory element may modulate susceptibility to a common complex disease.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectAllergyen_US
dc.subjectIL13en_US
dc.subjectPolymorphismen_US
dc.subjectT cellsen_US
dc.subjectTranscriotional Regulationen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGeneticsen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorVercelli, Donataen_US
dc.contributor.committeememberWysocki, Vickien_US
dc.contributor.committeememberRestifo, Lindaen_US
dc.contributor.committeememberMartinez, Fernandoen_US
dc.identifier.proquest10305en_US
dc.identifier.oclc752259932en_US
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