Integrative proteogenomics for differential expression and splicing variation in a DM1 mouse model

Solovyeva, E. M.; Utzinger, S.; Vissieres, A.; Mitchelmore, J.; Ahrne, E.; Hermes, E.; Poetsch, T.; Ronco, M.; Bidinosti, M.; Merkl, C.; Serluca, F.; Fessenden, J.; Naumann, U.; Voshol, H.; Meyer, A.; Hoersch, S.

doi:10.1101/2021.05.15.443842

bioRxiv · 10.1101/2021.05.15.443842

Integrative proteogenomics for differential expression and splicing variation in a DM1 mouse model

Solovyeva, E. M.·Utzinger, S.·Vissieres, A.·Mitchelmore, J.·Ahrne, E.·Hermes, E.·Poetsch, T.·Ronco, M.·Bidinosti, M.·Merkl, C.·Serluca, F.·Fessenden, J.·Naumann, U.·Voshol, H.·Meyer, A.·Hoersch, S.

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Abstract

Dysregulated mRNA splicing is involved in the pathogenesis of many diseases including cancer, neurodegenerative diseases, and muscular dystrophies such as myotonic dystrophy type 1 (DM1). Comprehensive assessment of dysregulated splicing on the transcriptome and proteome level has been methodologically challenging, and thus investigations have often been targeting only few genes. Here, we performed a large-scale coordinated transcriptomic and proteomic analysis to characterize a DM1 mouse model (HSALR) in comparison to wild-type. Our integrative proteogenomics approach comprised gene- and splicing-level assessments for mRNAs and proteins. It recapitulated many known instances of aberrant mRNA splicing in DM1 and identified new ones. It enabled the design and targeting of splicing-specific peptides and confirmed the translation of known instances of aberrantly spliced disease-related genes (e.g. Atp2a1, Bin1, Ryr1), complemented by novel findings (e.g. Ywhae, Flnc, Svil). Comparative analysis of large-scale mRNA and protein expression data showed quantitative agreement of differentially expressed genes and splicing patterns between disease and wild-type. We hence propose this work as a suitable blueprint for a robust and scalable integrative proteogenomic strategy geared towards advancing our understanding of splicing-based disorders. With such a strategy, splicing-based biomarker candidates emerge as an attractive and accessible option, as they can be efficiently asserted on the mRNA and protein level in coordinated fashion. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/443842v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@593246org.highwire.dtl.DTLVardef@1f3b5bforg.highwire.dtl.DTLVardef@12113b3org.highwire.dtl.DTLVardef@947d8f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Solovyeva, E. M., Utzinger, S., Vissieres, A., Mitchelmore, J., Ahrne, E., Hermes, E., Poetsch, T., Ronco, M., Bidinosti, M., Merkl, C., Serluca, F., Fessenden, J., Naumann, U., Voshol, H., Meyer, A., Hoersch, S.. 2021-05-16. Integrative proteogenomics for differential expression and splicing variation in a DM1 mouse model. https://doi.org/10.1101/2021.05.15.443842

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