| Abstract |
Studies on transcriptional regulation of liver specific genes have resulted in the identification of a set o transcription factors that determine their liver specific expression. These liver enriched hepatic regulators are HNF-1α,-1β,-3α,-3β,-3γ,-4α and -6, members of C/EBP και GATA families, as well as some nuclear receprors such as LRH-1 and COUP-TFII. In order to investigate the hierarchical networks that may operate during hepatocyte differentiation the present study was focused on mapping all of the crossregulatory interactions between the hepatic regulators during embryonic and postnatal liver development. In order to accomplish this we analyzed the expression levels of the 12 main hepatic regulators and the occupancy of their regulatory regions by each other after embryonic day 12.5, when the specification phase is complete and hepatoblast differentiation is taking place. We also performed a similar analysis in HNF-4α-deficient embryonic and adult mouse livers to assess the role of this central activator in the composition and stability of the network. The comprehensive map of interactions, combined with expression studies reveal that, during the studied developmental periods, cross-regulatory motifs are built up progressively to generate a highly flexible, self-sustaining transcription factor network. In summary the results of this study point to the progressive build-up of a highly interconnected transcription factor network during hepatocyte development. The network exhibits an unusually high level of plasticity in terms of regulatory effects, which provides the molecular basis for observations pertaining to dominant and redundant functions of its individual members. We have also studied the potential role of MAP kinase regulation on HNF-4 expression, and more specifically the effect of Erk2 activation in transcriptional regulation of ΗNF-4α in human hepatoma cells. We investigated the mechanism by which ΗNF-4α transcriptional status was changed as well as the role of C/EBPα in this mechanism.Taken together the data suggested that during MAP kinase activation the HNF-4 enhancer-promoter complex was disrupted. Upon the seizure of the signal, C/EBPα was re-expressed and the communication between the enhancer and the promoter was restored with parallel activation of transcription of the HNF-4α gene. Finally, we tried to accomplish a histological and phenotypical analysis of ΗNF-4αKO liver, in order to understand the role of ΗNF-4α in the maintenance of hepatic architecture and we focused on the study of genes that potentially are responsible for the disorganized hepatic phenotype. Τhe results of this study showed that HNF-4α has an essential role in the maintenance of hepatic phenotype and architecture and seems to be either directly or indirectly involved in the transcriptional regulation of genes coding for proteins which are responsible for cell to cell contacts.
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Αλληλορυθμιζόμενα μονοπάτια έκφρασης ηπατικών μεταγραφικών παραγόντων
