Mechanisms of messenger RNA splicing and RNA processing regulation

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PROJECT SUMMARY Messenger RNA splicing is carried out by a large macromolecular machine, the spliceosome, which undergoes dramatic rearrangements as it assembles onto a pre-messenger RNA. Our understanding of this elegant ribonucleoprotein machine has advanced significantly with the availability of cryoEM structures and an extensive “parts list” of splicing components. However, many questions remain about how spliceosome assembly takes place in the cell, where the spliceosome machinery assembles onto a nascent transcript that is being actively transcribed from a chromatin template, i.e. co-transcriptionally. Moreover, assembly of the spliceosome and splicing catalysis is tightly regulated and, in fact, there are widespread examples across eukaryotes of intron retention. Nonetheless, the regulatory consequences of this phenomenon remain obscure. Guided by strong preliminary data, we explore both of these outstanding challenges and address the following questions: (1) How does chromatin influence spliceosome assembly and vice versa, i.e. how does co-transcriptional spliceosome assembly affect the state of the chromatin? (2) How does intron retention contribute to gene regulation? (3) How does mis-regulation of intron accumulation lead to cellular toxicity and disease?