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

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 have 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 remarkable agreement of differential patterns between disease and wild-type on both the gene and especially the splicing level. We hence believe that our work is suitable as a model for a robust and scalable integrative proteogenomic strategy. This strategy provides investigative approaches, advances our understanding of the disease biology of splicing-based disorders, and helps establish robust splicing-specific biomarkers. ![Figure][1] ### Competing Interest Statement All authors except E.M.S. are employees of Novartis, and some hold Novartis stock. E.M.S. declares no conflicts. * DM1 : Myotonic Dystrophy, type 1 WT : wild-type Tx : Transcriptomics Px : Proteomics GE : Gene Expression DGE : Differential Gene Expression DAS : Differential Alternative Splicing RNA-seq : high-throughput mRNA sequencing FPKM : Fragments Per Kilobase of transcript per Million mapped reads (RNA-seq analysis) FC : fold change MS : Mass Spectrometry HPLC : High-Performance Liquid Chromatography DDA : Data-Dependent Acquisition TMT : Tandem Mass Tag PRM : Parallel Reaction Monitoring [1]: pending:yes