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

Autor:	Solovyeva EM; Research 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. Electronic address: elizaveta.solovyeva@novartis.com., Utzinger S; Diseases of Aging and Regenerative Medicine, Biomedical Research at Novartis, Basel, Switzerland., Vissières A; Discovery Sciences, Biomedical Research at Novartis, Basel, Switzerland., Mitchelmore J; Diseases of Aging and Regenerative Medicine, Biomedical Research at Novartis, Basel, Switzerland., Ahrné E; Discovery Sciences, Biomedical Research at Novartis, Basel, Switzerland., Hermes E; Discovery Sciences, Biomedical Research at Novartis, Basel, Switzerland., Poetsch T; Discovery Sciences, Biomedical Research at Novartis, Basel, Switzerland., Ronco M; Diseases of Aging and Regenerative Medicine, Biomedical Research at Novartis, Basel, Switzerland., Bidinosti M; Diseases of Aging and Regenerative Medicine, Biomedical Research at Novartis, Basel, Switzerland., Merkl C; Diseases of Aging and Regenerative Medicine, Biomedical Research at Novartis, Basel, Switzerland., Serluca FC; Research Informatics, Biomedical Research at Novartis, Cambridge, Massachusetts, USA., Fessenden J; Neurodegenerative Diseases, Biomedical Research at Novartis, Cambridge, Massachusetts, USA., Naumann U; Discovery Sciences, Biomedical Research at Novartis, Basel, Switzerland., Voshol H; Discovery Sciences, Biomedical Research at Novartis, Basel, Switzerland., Meyer AS; Diseases of Aging and Regenerative Medicine, Biomedical Research at Novartis, Basel, Switzerland., Hoersch S; Research Informatics, Biomedical Research at Novartis, Basel, Switzerland. Electronic address: sebastian.hoersch@novartis.com.
Jazyk:	angličtina
Zdroj:	Molecular & cellular proteomics : MCP [Mol Cell Proteomics] 2024 Jan; Vol. 23 (1), pp. 100683. Date of Electronic Publication: 2023 Nov 21.
DOI:	10.1016/j.mcpro.2023.100683
Abstrakt:	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 (HSA LR ) 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. Competing Interests: Conflict of interest All authors are employees of Novartis and some hold Novartis stock. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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