Mechanisms of transcriptional repression in Drosophila embryo development

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Cells are the fundamental units of life, and the unique character of individual cells is largely defined by the set of genes that is transcribed into various functional RNAs. Thus, the precise control of gene expression is highly important and dysregulated transcription underlies many diseases including cancer and neurological disorders. In eukaryotic cells, the DNA is highly compacted to fit into the limited volume of the nucleus. DNA-dependent processes such as transcription are repressed by this packaging of the DNA into chromatin. Therefore, till today, a lot of research was done to investigate transcriptional activation that overcomes this restriction, but much less to study transcriptional repression. However, regulation of gene expression by transcriptional repression is highly important for many key biological processes such as the generation of cellular diversity during embryo development. Since the mechanisms of transcriptional repression are largely unknown, the studying of these processes provides many opportunities to discover fundamental principles of gene control. First, we will perform comprehensive genome-wide repression profiling of transcriptomes and epigenomes to delineate different modes of repression and compare them between cells types. Secondly, we will determine the role of co-repressors in repression mechanisms by targeting them to enhancers using a modified CRISPR/Cas9 system. Third, we will characterise repression-related proteomes (repressome) and protein-protein interactions using biochemical and optical imaging techniques. Together, our work will provide new insights into the mechanisms underlying transcriptional repression that will be crucial for the development of new strategies to reprogram cell states and combat disease.