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1.
Mol Cell Proteomics ; 23(1): 100683, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37993104

RESUMO

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.


Assuntos
Distrofia Miotônica , Proteogenômica , Camundongos , Animais , Distrofia Miotônica/genética , Distrofia Miotônica/metabolismo , Distrofia Miotônica/patologia , Processamento Alternativo/genética , Proteômica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
2.
Nat Commun ; 12(1): 2442, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33903593

RESUMO

The transcription factor PAX8 is critical for the development of the thyroid and urogenital system. Comprehensive genomic screens furthermore indicate an additional oncogenic role for PAX8 in renal and ovarian cancers. While a plethora of PAX8-regulated genes in different contexts have been proposed, we still lack a mechanistic understanding of how PAX8 engages molecular complexes to drive disease-relevant oncogenic transcriptional programs. Here we show that protein isoforms originating from the MECOM locus form a complex with PAX8. These include MDS1-EVI1 (also called PRDM3) for which we map its interaction with PAX8 in vitro and in vivo. We show that PAX8 binds a large number of genomic sites and forms transcriptional hubs. At a subset of these, PAX8 together with PRDM3 regulates a specific gene expression module involved in adhesion and extracellular matrix. This gene module correlates with PAX8 and MECOM expression in large scale profiling of cell lines, patient-derived xenografts (PDXs) and clinical cases and stratifies gynecological cancer cases with worse prognosis. PRDM3 is amplified in ovarian cancers and we show that the MECOM locus and PAX8 sustain in vivo tumor growth, further supporting that the identified function of the MECOM locus underlies PAX8-driven oncogenic functions in ovarian cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteína do Locus do Complexo MDS1 e EVI1/genética , Neoplasias Ovarianas/genética , Fator de Transcrição PAX8/genética , Animais , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Proteína do Locus do Complexo MDS1 e EVI1/metabolismo , Camundongos Nus , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Fator de Transcrição PAX8/metabolismo , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
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