Thank you!

We would also like to thank @narjournal.bsky.social 's editorial team and reviewers for their feedback and support!

Let us know what you think! We’re very excited to see how our approach can lead to new insights for you!

This work would not have been possible without my super supervisors, Samuel Miravet-Verde & Luis Serrano and the Serrano Lab team, at the wonderful @crg.eu

Although more validation will be needed, we believe our work will enable studying the state of splicing factors in widely available and single-cell atlases, contributing to providing a more complete picture of splicing regulation in data-scarce but experimentally very rich settings.

Interestingly, during embryogenesis, the regulation of splicing factors follows the opposite trend from that observed during carcinogenesis. MYC, G2M, and E2F prioritized pathways are downregulated during human embryogenesis, supporting their role as regulators of the carcinogenic switch of SFs.

Because our prioritization involved Perturb-seq experiments, we could ask which other pathways had also strong evidence as mediators. These were: G2M checkpoint, E2F targets, and spermatogenesis.

Long story short, the MYC pathway was the top candidate, further supporting the known importance of MYC in regulating splicing (great references: Leclair et al. 2022 ( @olgaanczukow.bsky.social lab) and Koh et al. 2015 ( @guccionelab.bsky.social lab)).

But most cancer-driver mutations don’t involve splicing factors, so how does cancer induce this aberrant regulation in splicing factors?

We came up with a strategy to isolate the best candidate pathways connecting cancer-driver mutations and carcinogenic splicing factor regulation.

A nice insight was to see that not one but many splicing factors can drive their own aberrant regulation. We found evidence that they do so through their splicing factor-exon and protein-protein interactions.

Through Perturb-seq datasets in RPE1 pre-cancerous cells (Replogle et al. 2022 ( @weissmanlab.bsky.social )), we could dissect systematically which genes drive carcinogenesis regulation of splicing factors.

This enabled us to use existing datasets to explore how splicing factors are regulated during carcinogenesis in bulk (Danielsson et al. 2013 (Emma Lundberg lab)) and single-cell models (Hodis et al. 2022 (Aviv Regev lab)).

Building on our method for splicing factor activity analysis (doi.org/10.1101/2024...), we expand our database of experiments that perturb SFs and show that adjusting SF activities with a “shallow” neural net does well at recapitulating exon-inclusion-based activities from only gene expression.

@splicingnews.bsky.social

@splicingnews.bsky.social