PT  - JOURNAL ARTICLE
AU  - Elizaveta M. Solovyeva
AU  - Stephan Utzinger
AU  - Alexandra Vissières
AU  - Joanna Mitchelmore
AU  - Erik Ahrné
AU  - Erwin Hermes
AU  - Tania Poetsch
AU  - Marie Ronco
AU  - Michael Bidinosti
AU  - Claudia Merkl
AU  - Fabrizio C. Serluca
AU  - James Fessenden
AU  - Ulrike Naumann
AU  - Hans Voshol
AU  - Angelika Meyer
AU  - Sebastian Hoersch
TI  - Integrative proteogenomics for differential expression and splicing variation in a DM1 mouse model
AID  - 10.1101/2021.05.15.443842
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.05.15.443842
4099  - http://biorxiv.org/content/early/2021/05/16/2021.05.15.443842.short
4100  - http://biorxiv.org/content/early/2021/05/16/2021.05.15.443842.full
AB  - 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.Competing Interest StatementAll authors except E.M.S. are employees of Novartis, and some hold Novartis stock. E.M.S. declares no conflicts.DM1Myotonic Dystrophy, type 1WTwild-typeTxTranscriptomicsPxProteomicsGEGene ExpressionDGEDifferential Gene ExpressionDASDifferential Alternative SplicingRNA-seqhigh-throughput mRNA sequencingFPKMFragments Per Kilobase of transcript per Million mapped reads (RNA-seq analysis)FCfold changeMSMass SpectrometryHPLCHigh-Performance Liquid ChromatographyDDAData-Dependent AcquisitionTMTTandem Mass TagPRMParallel Reaction Monitoring