RT Journal Article
SR Electronic
T1 Quantitative proteomics reveals key roles for post-transcriptional gene regulation in the molecular pathology of FSHD
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 417790
DO 10.1101/417790
A1 Sujatha Jagannathan
A1 Yuko Ogata
A1 Philip R. Gafken
A1 Stephen J. Tapscott
A1 Robert K. Bradley
YR 2018
UL http://biorxiv.org/content/early/2018/09/14/417790.abstract
AB 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.