Integrative Proteogenomics for Differential Expression and Splicing Variation in a DM1 Mouse Model

• Published in: Molecular & cellular proteomics 2024-01, Vol.23 (1), p.100683-100683, Article 100683
• Main Authors: Solovyeva, Elizaveta M., Utzinger, Stephan, Vissières, Alexandra, Mitchelmore, Joanna, Ahrné, Erik, Hermes, Erwin, Poetsch, Tania, Ronco, Marie, Bidinosti, Michael, Merkl, Claudia, Serluca, Fabrizio C., Fessenden, James, Naumann, Ulrike, Voshol, Hans, Meyer, Angelika S., Hoersch, Sebastian
• Format: Article
• Language: English
• Subjects: alternative splicing; myotonic dystrophy type 1 (DM1); proteogenomics
• ISSN: 1535-9476; 1535-9484
• DOI: 10.1016/j.mcpro.2023.100683

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 (Flnc and Ywhae). 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 toward 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. [Display omitted] •Performed large-scale proteogenomic analysis of DM1 mouse model (HSALR).•Identified and confirmed known and novel instances of aberrant mRNA splicing in DM1.•Showed agreement of dysregulated splicing patterns on transcript and protein level. Dysregulated mRNA splicing is involved in many diseases including myotonic dystrophy type 1 (DM1). Our proteogenomics analysis of DM1 mouse model (HSALR) comprised gene- and splicing-level assessments for mRNAs and proteins. 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 (Flnc and Ywhae). Comparative analysis between transcriptomics and proteomics showed good quantitative agreement of differentially expressed genes and splicing patterns.