Abstract
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.
Highlights
Facioscapulohumeral muscular dystrophy (FSHD) is caused by the inappropriate expression of an early embryonic transcriptional activator, DUX4, in adult muscle, leading to cell death (Tawil et al, 2014; Lemmers et al, 2010)
We previously showed that comparable gene expression profiles, which accurately capture the transcriptome of facioscapulohumeral muscular dystrophy (FSHD) cells, are produced when DUX4 is expressed either via a lentiviral vector or when an inducible transgene is integrated into the genome of a myoblast cell line (Jagannathan et al, 2016)
We found that DUX4-expressing cells showed severe fragmentation of their Golgi apparatus, which could be an indicator of a perturbation in the cellular secretory pathways (Bexiga and Simpson, 2013) (Figure 2D)
Summary
Facioscapulohumeral muscular dystrophy (FSHD) is caused by the inappropriate expression of an early embryonic transcriptional activator, DUX4, in adult muscle, leading to cell death (Tawil et al, 2014; Lemmers et al, 2010). Decades of work have generated a detailed list of the genes and pathways affected by DUX4 that may underlie FSHD pathophysiology (Geng et al, 2012; Block et al, 2013; Young et al, 2013; Banerji et al, 2015; Feng et al, 2015; Homma et al, 2015; Dmitriev et al, 2016; Shadle et al, 2017). DUX4 induces changes in the expression of hundreds of genes that impact dozens of highly interconnected pathways
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
