KUKU

KU ScholarWorks

  • myKU
  • Email
  • Enroll & Pay
  • KU Directory
    • Login
    View Item 
    •   KU ScholarWorks
    • Dissertations and Theses
    • Theses
    • View Item
    •   KU ScholarWorks
    • Dissertations and Theses
    • Theses
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Developmental regulation of the human beta-globin locus and the role of the O and P regions in beta-like globin gene expression

    Thumbnail
    View/Open
    Bomhoff_Anna_Louise_2007_5349263.pdf (1.564Mb)
    Issue Date
    2007-05-31
    Author
    Bomhoff, Anna Louise
    Publisher
    University of Kansas
    Type
    Thesis
    Degree Level
    M.S.
    Discipline
    Biochemistry and Molecular Biology
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
    Metadata
    Show full item record
    Abstract
    The human β-globin locus is a highly complex genetic system that has become a classical model for studying the regulation of eukaryotic gene expression. The locus consists of five functional β-like globin genes, ϵ- Gγ-Aγ-δ-β and a powerful upstream regulatory element, the locus control region (LCR) that is physically composed of five DNase-I hypersensitive sites. The globin genes are regulated in a tissue and developmental stage-specific manner and are arranged spatially in the order in which they are expressed during development. During development two switches in globin gene expression occur to accommodate the changing oxygen needs of the fetus. The first switch from embryonic ϵ- to fetal γ-globin occurs at six weeks of gestation and the second switch from γ-globin to adult β- and δ-globin occurs shortly after birth. Intense studies of globin gene expression over the past two decades have enhanced our understanding considerably of the molecular mechanisms that together ensure a highly specialized, tissue- and stage-specific transcription pattern of the β-like genes during development. From these studies many of the key players at the human β-globin locus have been identified. They include the cis-acting regulatory elements, such as the LCR and gene-proximal regulatory sequences, involved in establishing and maintaining specific chromatin conformations and histone modification patterns throughout the locus, and transcriptional activation, as well as trans-acting factors, both erythroid-specific and general. Much of the current research on the human β-globin locus has been focused on further elucidating the mechanisms involved in the regulation of the fetal γ-globin genes in an effort to develop potential therapies that will enhance fetal hemoglobin expression in individuals with sickle cell disease or β-thalassemia. Therefore, two regions, O and P, located upstream of the δ-globin gene, that had previously been shown to function as silencers of the γ-globin genes in transient transfection assays were investigated. We hypothesized that if the O and P regions do in fact function to silence the γ-globin genes during development, then the deletion of these regions from the human β-globin locus would result in the persistence of γ-globin in the adult erythroid cells To test this hypothesis, the O and P regions were deleted from a 213 kb human β-globin locus yeast artificial chromosome (β-YAC). Transgenic mice were produced with the modified β-YAC and the effects of this OP deletion on expression of the human β-like globin genes were analyzed. Deletion of these regions resulted in the abolishment of ϵ-globin gene expression during embryonic erythropoiesis and a substantial decrease in β-globin globin gene expression during definitive erythropoiesis. Conversely, expression of the γ-globin genes was only slightly affected during fetal definitive erythropoiesis. Although these results do not indicate that the O and P regions are involved in silencing the γ-globin genes during development, they do provide some insight into the role of these regions in the regulation of the β-like globin genes.
    Description
    Thesis (M.S.)--University of Kansas, Biochemistry and Molecular Biology, 2007.
    URI
    http://hdl.handle.net/1808/31962
    Collections
    • Theses [3827]

    Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.


    We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.


    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    Browse

    All of KU ScholarWorksCommunities & CollectionsThis Collection

    My Account

    LoginRegister

    Statistics

    View Usage Statistics

    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    The University of Kansas
      Contact KU ScholarWorks
    Lawrence, KS | Maps
     
    • Academics
    • Admission
    • Alumni
    • Athletics
    • Campuses
    • Giving
    • Jobs

    The University of Kansas prohibits discrimination on the basis of race, color, ethnicity, religion, sex, national origin, age, ancestry, disability, status as a veteran, sexual orientation, marital status, parental status, gender identity, gender expression and genetic information in the University’s programs and activities. The following person has been designated to handle inquiries regarding the non-discrimination policies: Director of the Office of Institutional Opportunity and Access, IOA@ku.edu, 1246 W. Campus Road, Room 153A, Lawrence, KS, 66045, (785)864-6414, 711 TTY.

     Contact KU
    Lawrence, KS | Maps