Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophy
DUX4 is a transcription factor whose misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). DUX4’s transcriptional activity has been extensively characterized, but the DUX4-induced proteome remains undescribed. Here, we report concurrent measurement of RNA and protein...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/41740 |
| _version_ | 1811252981112242176 |
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| author | Sujatha Jagannathan Yuko Ogata Philip R Gafken Stephen J Tapscott Robert K Bradley |
| author_facet | Sujatha Jagannathan Yuko Ogata Philip R Gafken Stephen J Tapscott Robert K Bradley |
| author_sort | Sujatha Jagannathan |
| collection | DOAJ |
| description | DUX4 is a transcription factor whose misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). DUX4’s transcriptional activity has been extensively characterized, but the DUX4-induced proteome remains undescribed. Here, we report concurrent measurement of RNA and protein levels in DUX4-expressing cells via RNA-seq and quantitative mass spectrometry. DUX4 transcriptional targets were robustly translated, confirming the likely clinical relevance of proposed FSHD biomarkers. However, a multitude of mRNAs and proteins exhibited discordant expression changes upon DUX4 expression. Our dataset revealed unexpected proteomic, but not transcriptomic, dysregulation of diverse molecular pathways, including Golgi apparatus fragmentation, as well as extensive post-transcriptional buffering of stress-response genes. Key components of RNA degradation machineries, including UPF1, UPF3B, and XRN1, exhibited suppressed protein, but not mRNA, levels, explaining the build-up of aberrant RNAs that characterizes DUX4-expressing cells. Our results provide a resource for the FSHD community and illustrate the importance of post-transcriptional processes in DUX4-induced pathology. |
| first_indexed | 2024-04-12T16:42:54Z |
| format | Article |
| id | doaj.art-0ef1432bc86143f6b7218ee81a8d4607 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:42:54Z |
| publishDate | 2019-01-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj.art-0ef1432bc86143f6b7218ee81a8d46072022-12-22T03:24:41ZengeLife Sciences Publications LtdeLife2050-084X2019-01-01810.7554/eLife.41740Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophySujatha Jagannathan0https://orcid.org/0000-0001-9039-2631Yuko Ogata1Philip R Gafken2Stephen J Tapscott3https://orcid.org/0000-0002-0319-0968Robert K Bradley4https://orcid.org/0000-0002-8046-1063Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United StatesProteomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, United StatesProteomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, United StatesHuman Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United StatesComputational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United StatesDUX4 is a transcription factor whose misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). DUX4’s transcriptional activity has been extensively characterized, but the DUX4-induced proteome remains undescribed. Here, we report concurrent measurement of RNA and protein levels in DUX4-expressing cells via RNA-seq and quantitative mass spectrometry. DUX4 transcriptional targets were robustly translated, confirming the likely clinical relevance of proposed FSHD biomarkers. However, a multitude of mRNAs and proteins exhibited discordant expression changes upon DUX4 expression. Our dataset revealed unexpected proteomic, but not transcriptomic, dysregulation of diverse molecular pathways, including Golgi apparatus fragmentation, as well as extensive post-transcriptional buffering of stress-response genes. Key components of RNA degradation machineries, including UPF1, UPF3B, and XRN1, exhibited suppressed protein, but not mRNA, levels, explaining the build-up of aberrant RNAs that characterizes DUX4-expressing cells. Our results provide a resource for the FSHD community and illustrate the importance of post-transcriptional processes in DUX4-induced pathology.https://elifesciences.org/articles/41740facioscapulohumeral muscular dystrophynonsense-mediated RNA decaypost-transcriptional gene regulationDUX4FSHDNMD |
| spellingShingle | Sujatha Jagannathan Yuko Ogata Philip R Gafken Stephen J Tapscott Robert K Bradley Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophy eLife facioscapulohumeral muscular dystrophy nonsense-mediated RNA decay post-transcriptional gene regulation DUX4 FSHD NMD |
| title | Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophy |
| title_full | Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophy |
| title_fullStr | Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophy |
| title_full_unstemmed | Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophy |
| title_short | Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophy |
| title_sort | quantitative proteomics reveals key roles for post transcriptional gene regulation in the molecular pathology of facioscapulohumeral muscular dystrophy |
| topic | facioscapulohumeral muscular dystrophy nonsense-mediated RNA decay post-transcriptional gene regulation DUX4 FSHD NMD |
| url | https://elifesciences.org/articles/41740 |
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