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Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of FSHD

View ORCID ProfileSujatha Jagannathan, Yuko Ogata, Philip R. Gafken, View ORCID ProfileStephen J. Tapscott, View ORCID ProfileRobert K. Bradley
doi: https://doi.org/10.1101/417790
Sujatha Jagannathan
1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
3Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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  • For correspondence: rbradley@fredhutch.org sujatha.jagannathan@ucdenver.edu stapscot@fredhutch
Yuko Ogata
4Proteomics Facility, Fred Hutchinson Cancer Research Center
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Philip R. Gafken
4Proteomics Facility, Fred Hutchinson Cancer Research Center
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Stephen J. Tapscott
3Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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  • ORCID record for Stephen J. Tapscott
  • For correspondence: rbradley@fredhutch.org sujatha.jagannathan@ucdenver.edu stapscot@fredhutch
Robert K. Bradley
1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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  • For correspondence: rbradley@fredhutch.org sujatha.jagannathan@ucdenver.edu stapscot@fredhutch
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Abstract

DUX4 is a transcription factor whose misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). While DUX4’s transcriptional activity has been extensively characterized, 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 machinery, 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 process to DUX4-induced pathology.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 29, 2018.
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Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of FSHD
Sujatha Jagannathan, Yuko Ogata, Philip R. Gafken, Stephen J. Tapscott, Robert K. Bradley
bioRxiv 417790; doi: https://doi.org/10.1101/417790
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Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of FSHD
Sujatha Jagannathan, Yuko Ogata, Philip R. Gafken, Stephen J. Tapscott, Robert K. Bradley
bioRxiv 417790; doi: https://doi.org/10.1101/417790

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