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

Elife. 2019 Jan 15:8:e41740. doi: 10.7554/eLife.41740.


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.

Keywords: DUX4; FSHD; NMD; facioscapulohumeral muscular dystrophy; genetics; genomics; human; human biology; medicine; nonsense-mediated RNA decay; post-transcriptional gene regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Gene Expression Regulation*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Muscular Dystrophy, Facioscapulohumeral / genetics*
  • Muscular Dystrophy, Facioscapulohumeral / metabolism*
  • Proteomics / methods*
  • RNA / genetics
  • RNA / metabolism
  • Stress, Physiological / genetics
  • Transcription, Genetic*


  • DUX4L1 protein, human
  • Homeodomain Proteins
  • RNA