Unknown,Transcriptomics,Genomics,Proteomics

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Expression profiling data of RD and C2C12 cells ectopically expressing DUX4

ABSTRACT: Transcriptomic changes induced by DUX4 expression were compared between human and mouse cell lines of muscle lineage. We used microarrays to compare transcripts induced in human rhabdmyosarcoma and mouse C2C12 cells ectopically expressing DUX4. Human rhabdomyosarcoma and mouse C2C12 cells were transfected with DUX4 expression vectors (n=4). Cells transfected with insertless vectors were used as controls. Samples were processed for RNA extraction 16 hours following transfection.

ORGANISM(S): Mus musculus

SUBMITTER: Yi-Wen Chen

PROVIDER: E-GEOD-45854 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:DUX4 is a double homeodomain transcription factor whose misexpression in the muscle causes facioscapulohumeral muscular dystrophy (FSHD). The transcriptional activity of DUX4 has been extensively characterized, and is thought to be the primary driver of FSHD pathogenesis. Yet, DUX4 expression lowers the protein level of an RNA quality control factor, UPF1, without affecting its transcript level, hinting at post-transcriptional regulatory activity downstream of DUX4 expression. How extensive the post-transcriptional activity of DUX4 is, and how relevant it is to FSHD pathogenesis, is unknown. In order to gain insight into DUX4-induced post-transcriptional gene regulation, we measured transcript and protein levels in DUX4 expressing cells via RNA-seq and SILAC-based quantitative mass spectrometry, respectively. We show that DUX4 transcriptional targets are robustly translated, including those genes previously identified as potential FSHD biomarkers. However, comparing the overall pattern of gene expression changes for RNA versus protein reveals striking differences in the most highly activated pathways, with the former showing changes in RNA processing and splicing, and the latter affecting the humoral immune response, proteolysis and exocytosis, among other pathways. Consistent with a misregulation of exocytosis, fluorescence imaging shows fragmented golgi apparatus in DUX4-expressing cells. Of the genes that showed discordant RNA and protein expression levels, post-transcriptional buffering was particularly evident for genes involved in stress response and may explain why DUX4-expressing cells succumb to toxicity despite robust transcriptional activation of stress response genes. Moreover, several genes involved in RNA decay including UPF1, UPF3B, SMG6 and XRN1 showed downregulation at the protein level, which may explain the massive inhibition of RNA quality control in DUX4-expressing cells. These results highlight the importance of considering post-transcriptional gene regulation in DUX4-expressing cells in order to fully understand the FSHD disease process.

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Expression profiling data of RD and C2C12 cells ectopically expressing DUX4

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