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An integrative bioinformatics approach for analyses of multi-level transcriptional regulation and three-dimensional organization in the epidermis and skin appendages. Exploring genomic transcriptional profiles of the distinct stages of hair follicle and sweat gland development and analyses of mechanism integrating the transcriptional regulation, linear and high-order genome organization within epidermal differentiation complex in keratinocytes.

Publication Date
2013-11-04
End of Embargo
Supervisor
Botchkarev, Vladimir A.
Peng, Yonghong
Keywords
Bioinformatics, Microarray, ChIP-on-chip, Chromosome conformation capture carbon copy, Chromosome conformation capture carbon copy (5c), Transcriptional regulation, Three-dimensional genome organization, Hair follicle, Sweat gland, Keratinocytes
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Creative Commons License
The University of Bradford theses are licenced under a Creative Commons Licence.
Peer-Reviewed
Open Access status
Accepted for publication
Institution
University of Bradford
Department
School of Life Sciences
Awarded
2013
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Abstract
The transcription in the eukaryotic cells involves epigenetic regulatory mechanisms that control local and higher-order chromatin remodelling. In the skin, keratinocyte-specific genes are organized into distinct loci including Epidermal Differentiation Complex (EDC) and Keratin type I/II loci. This thesis introduces bioinformatics approaches to analyze multi-level regulatory mechanisms that control skin development and keratinocyte-specific differentiation. Firstly, integration of gene expression data with analyses of linear genome organization showed dramatic downregulation of the genes that comprise large genomic domains in the sweat glands including EDC locus, compared to ii hair follicles, suggesting substantial differences in global genome rearrangement during development of these two distinct skin appendages. Secondly, comparative analysis of the genetic programmes regulated in keratinocytes by Lhx2 transcription factor and chromatin remodeler Satb1 revealed that significant number of their target genes is clustered in the genome. Furthermore, it was shown in this study that Satb1 target genes are lineage-specific. Thirdly, analysis of the topological interactomes of Loricrin and Keratin 5 in hair follicle steam cells revealed presence of the cis- and trans-interactions and lineage specific genes (Wnt, TGF-beta/activin, Notch, etc.). Expression levels of the genes that comprise interactomes show correlation with their histone modification status. This study demonstrates the crucial role for integration of transcription factormediated and epigenetic regulatory mechanisms in establishing a proper balance of gene expression in keratinocytes during development and differentiation into distinct cell lineages and provides an integrated bioinformatics platform for further analyses of the changes in global organization of keratinocyte-specific genomic loci in normal and diseased skin.
URI
http://hdl.handle.net/10454/5658
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Type
Thesis
Qualification name
PhD
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