Abstract
Gene expression is regulated at multiple levels to ensure coordinated synthesis of the cells’ macromolecular components. Besides transcriptional regulation, the control of the later post-transcriptional steps has substantial impact on gene expression with widespread implications in physiologically important processes such as development, metabolism, neuronal function, and for cancer progression. On the one hand, posttranscriptional regulation is mediated by RNA-binding proteins (RBPs), which control almost every aspect of RNA’s life in a dynamic manner from RNA maturation, quality control, localization, translation, and degradation. On the other hand, mRNAs are post-transcriptionally regulated via physical interactions with small non-coding RNAs. The best characterized class of such RNAs are microRNAs (miRNAs), ~22 nucleotide long RNA molecules that negatively regulate gene expression. Hundreds of RNA-binding proteins (RBPs) and miRNAs are present in eukaryotic genomes, rivaling in number other classes of regulatory molecules such as transcription factors and kinases and thus, suggests and elaborate system for post-transcriptional control that may affect virtually every message in a cell. Whereas many classical studies explored the molecular function and physiological impact of post-transcriptional regulation on specific mRNA substrates, the recent development of genome-wide analysis tools enables now to study the extend and logic of post-transcriptional gene regulation (PTGR) on a global scale. I have pioneered such ‘ribonomic’ studies and established methods to affinity isolate RNA-binding proteins and systematically analyzed bound RNAs with DNA microarrays for more than 50 RBPs from yeast, flies, and humans. These studies revealed that RBPs preferentially associate with messages that share common functional and structural attributes suggesting the presence of a highly complex and interweaved post-transcriptional regulatory system. In addition, unraveling the RNA targets for particular RBPs has lead to new insights into their molecular and physiological function. In this habilitation thesis, I summarize some of these investigations and provide an outlook for future research and potential applications for pharmaceutical sciences.