Molecular mechanisms of gene regulation in response to environmental and developmental stimuli
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Abstract
Biological processes such as cellular differentiation or response to environmental stimuli require gene expression adaptations. Such plastic remodeling is achieved by the application of diverse mechanisms that involve transcriptional and epigenetic modulations. In order to gain deeper insights into the molecular changes, the expression and chromatin alterations occurring in response to UV irradiation, circadian rhythm and neuronal cell fate commitment were investigated in this thesis. To this end, molecular experiments and high-throughput sequencing techniques were applied along with bioinformatics and mathematical modeling analyses. These comprehensive investigations have revealed multiple, interconnected processes that regulate diverse gene expression variations upon exposure to stimuli. As a consequence of UV irradiation, the chromatin in fibroblasts underwent drastic alterations. This included a genome-wide loss of chromatin accessibility as well as a reorganization of the histone modification H3K27ac. These epigenetic variations could explain the observed expression changes of numerous genes. In the context of circadian rhythm, transcription factors and epigenetic regulators with a circadian expression pattern were identified. These factors represent putative regulators of the core clock network (e.g., ZFP28) or other genes that display a circadian expression (e.g., ZFP28 and LEO1). Furthermore, this thesis highlights a fate commitment role of PAX6 in neural progenitor cells, where it acts as a gatekeeper by directly or indirectly activating ectodermal genes and repressing genes that are important for other linages. Additionally, a novel PAX6 target, Ift74, was demonstrated to be required for in vivo neurogenesis. In summary, this thesis revealed diverse, especially chromatin-mediated mechanisms, which cells utilize to respond to stimuli. Moreover, it contributes towards the understanding of the underlying gene regulatory networks.