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Integrative Proteogenomics for Differential Expression and Splicing Variation in a DM1 Mouse Model.
Elizaveta M Solovyeva1, Stephan Utzinger2, Alexandra Vissières3
1Research Informatics, Biomedical Research at Novartis, Basel, Switzerland; V.L. Talrose Institute for Energy Problems of Chemical Physics, N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, Moscow, Russia.
Dysregulated mRNA splicing contributes to diseases like myotonic dystrophy type 1 (DM1). This study presents a scalable proteogenomic strategy to comprehensively analyze splicing changes at both mRNA and protein levels, identifying new disease-related targets.
Area of Science:
- Molecular Biology
- Genomics
- Proteomics
Background:
- Dysregulated mRNA splicing is implicated in numerous diseases, including cancer, neurodegenerative disorders, and muscular dystrophies like myotonic dystrophy type 1 (DM1).
- Comprehensive assessment of splicing alterations at both transcriptomic and proteomic levels has been methodologically challenging, often limiting studies to a few genes.
Purpose of the Study:
- To perform a large-scale, coordinated transcriptomic and proteomic analysis in a myotonic dystrophy type 1 (DM1) mouse model (HSALR) compared to wild-type controls.
- To develop and validate a robust and scalable integrative proteogenomic strategy for studying splicing-based disorders.
Main Methods:
- Utilized an integrative proteogenomics approach, assessing both gene and splicing levels for mRNAs and proteins.
- Conducted comparative analysis of large-scale mRNA and protein expression data between DM1 model and wild-type mice.
- Enabled design and targeting of splicing-specific peptides based on findings.
Main Results:
- Recapitulated known aberrant mRNA splicing events in DM1 and identified novel instances.
- Confirmed translation of aberrantly spliced disease-related genes (e.g., Atp2a1, Bin1, Ryr1) and discovered new ones (Flnc, Ywhae).
- Demonstrated quantitative agreement in differentially expressed genes and splicing patterns between disease and wild-type states at both mRNA and protein levels.
Conclusions:
- The proposed integrative proteogenomic strategy offers a blueprint for advancing the understanding of splicing-based disorders.
- Splicing-based biomarker candidates are identified as accessible options, verifiable at both mRNA and protein levels.
- This approach facilitates a comprehensive understanding of disease pathogenesis driven by splicing dysregulation.
