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.

摘要

The transcription in the eukaryotic cells involves epigenetic regulatoryudmechanisms that control local and higher-order chromatin remodelling. In theudskin, keratinocyte-specific genes are organized into distinct loci includingudEpidermal Differentiation Complex (EDC) and Keratin type I/II loci. This thesisudintroduces bioinformatics approaches to analyze multi-level regulatoryudmechanisms that control skin development and keratinocyte-specificuddifferentiation.udFirstly, integration of gene expression data with analyses of linear genomeudorganization showed dramatic downregulation of the genes that compriseudlarge genomic domains in the sweat glands including EDC locus, compared toudiiudhair follicles, suggesting substantial differences in global genome rearrangementudduring development of these two distinct skin appendages.udSecondly, comparative analysis of the genetic programmes regulated inudkeratinocytes by Lhx2 transcription factor and chromatin remodeler Satb1udrevealed that significant number of their target genes is clustered in theudgenome. Furthermore, it was shown in this study that Satb1 target genes areudlineage-specific.udThirdly, analysis of the topological interactomes of Loricrin and Keratin 5 inudhair follicle steam cells revealed presence of the cis- and trans-interactionsudand lineage specific genes (Wnt, TGF-beta/activin, Notch, etc.). Expressionudlevels of the genes that comprise interactomes show correlation with theirudhistone modification status.udThis study demonstrates the crucial role for integration of transcription factormediatedudand epigenetic regulatory mechanisms in establishing a properudbalance of gene expression in keratinocytes during development anduddifferentiation into distinct cell lineages and provides an integratedudbioinformatics platform for further analyses of the changes in globaludorganization of keratinocyte-specific genomic loci in normal and diseasedudskin.