Architecture and Remodelling of the Cotranscriptional Spliceosome

Ziel

Pre-mRNA splicing is an essential step in gene expression, executed by the spliceosome—one of the most intricate molecular machines in eukaryotic cells. Splicing occurs predominantly co-transcriptionally, in close coordination with RNA Polymerase II. Yet, the molecular mechanisms that underlie this coupling remain poorly understood.

This project seeks to uncover how the transcription machinery directs and coordinates spliceosome assembly and activation. Our central hypothesis is that dynamic interactions with Pol II orchestrate both spliceosome formation and catalytic progression, thereby enabling co-transcriptional splicing to proceed with greater efficiency and fidelity than splicing in isolation.

Recent cryo-EM studies have resolved major spliceosomal intermediates, but these structures were obtained from RNA substrates outside their native transcriptional context. This represents a critical gap in our understanding of how spliceosome dynamics are integrated with ongoing transcription.

To address this, we will reconstitute and isolate key stages of the co-transcriptional splicing pathway and analyze their structures using cryo-EM and complementary integrative approaches. This strategy will reveal how spliceosomes are physically and functionally coupled to Pol II, and how their architecture and composition remodel during the splicing cycle.

By elucidating the structural logic of co-transcriptional splicing, this project will provide fundamental insights into gene regulation and uncover general principles that extend to RNA processing and expression control.

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