Functional analysis of regulated mRNA 3'end processing in the control of inflammatory processes, innate immunity and tumorigenesis

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Posttranscriptional mechanisms that control gene expression play an increasingly recognized role in health and disease1-6. While substantial progress has been made to characterize many of these mechanisms, the regulation of mRNA 3’end processing is still poorly understood. Importantly, alternative and regulated mRNA 3’end processing modulates the expression of many genes7,8, often in response to extracellular stimuli6,8-10. Despite these findings, the involved signal-transduction pathways and their role to execute specific cellular programs are unknown. I will integrate bioinformatical, biochemical and functional genomic approaches to dissect the molecular and cellular mechanisms of regulated mRNA 3’end processing. We will identify functionally relevant factors and signaling pathways that modulate this step of mRNA processing in response to external stimuli. Furthermore, we will explore whether a novel class of transcripts, in which 3’end processing is activated by specific sequence elements6,11-19, represents a functionally coupled RNA operon to execute cellular programs in response to external stimuli20,21. Interestingly, this class includes many transcripts with key roles in inflammation and tumorigenesis. These findings will be translated into disease models that could ultimately provide novel insights into in vivo-validated targets and/or signaling components for therapeutic intervention.