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    Epigenetic Regulation of Skin Development and Postnatal Homeostasis The role of chromatin architectural protein Ctcf in the control of Keratinocyte Differentiation and Epidermal Barrier Formation

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    PhD Thesis (4.907Mb)
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    Publication date
    2018-02-01
    Author
    Malashchuk, Igor
    Supervisor
    Botchkarev, Vladimir A.
    Mardaryev, Andrei N.
    Fessing, Michael Y.
    Keyword
    Three dimensional genome organisation; Skin; Ctcf (Chromatin architectural protein); Microarray; Fluorescent in situ hybridization; Epigenetic regulation; Epidermal barrier
    Rights
    Creative Commons License
    The University of Bradford theses are licenced under a Creative Commons Licence.
    Institution
    University of Bradford
    Department
    School of Medical Sciences
    Awarded
    2016
    
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    Abstract
    Epigenetic regulatory mechanisms play important roles in the control of lineage-specific differentiation during development. However, mechanisms that regulate higher-order chromatin remodelling and transcription of keratinocyte-specific genes that are clustered in the genome into three distinct loci (Keratin type I/II loci and Epidermal Differentiation Complex (EDC) during differentiation of the epidermis are poorly understood. By using 3D-Fluorescent In Situ Hybridization (FISH), we determined that in the epidermal keratinocytes, the KtyII and EDC loci are located closely to each other in the nuclear compartment enriched by the nuclear speckles. However, in KtyII locus knockout mice, EDC locus moved away from the KtyII locus flanking regions and nuclear speckles towards the nuclear periphery, which is associated with marked changes in gene expression described previously. Chromatin architectural protein Ctcf has previously been implicated in the control of long-range enhancer-promoter contacts and inter-chromosomal interactions. Ctcf is broadly expressed in the skin including epidermal keratinocytes and hair follicles. Conditional Keratin 14-driven Ctcf ablation in mice results in the increase of the epidermal thickness, proliferation, alterations of the epidermal barrier and the development of epidermal pro-inflammatory response. Epidermal barrier defects in Krt14CreER/Ctcf fl/fl mice are associated with marked changes in gene expression in the EDC and KtyII loci, which become topologically segregated in the nucleus upon Ctcf ablation. Therefore, these data suggest that Ctcf serves as critical determinant regulating higher-order chromatin organization in lineage-specific gene loci in epidermal keratinocytes, which is required for the proper control of gene expression, maintenance of the epidermal barrier and its function.
    URI
    http://hdl.handle.net/10454/14791
    Type
    Thesis
    Qualification name
    PhD
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    Theses

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