Dataset Information

MOE silencing of DUX4 in FSHD and UASB myoblasts

ABSTRACT: Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight to disease mechanisms underpinned by post-transcriptional processes. We used stable isotope (deuterium oxide; D2O) labelling and peptide mass spectrometry to investigate the abundance and turnover rates of proteins in cultured muscle cells from 2 individuals affected by FSHD and their unaffected siblings (UASb). Cells were treated with or without MOE to silence DUX4

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Striated Visceral Muscle Cell, Cell Culture

DISEASE(S): Facioscapulohumeral Muscular Dystrophy

SUBMITTER: Jatin Burniston

LAB HEAD: Jatin G Burniston

PROVIDER: PXD042374 | Pride | 2023-06-27

REPOSITORIES: pride

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Publications

Facioscapulohumeral Muscular Dystrophy is Associated With Altered Myoblast Proteome Dynamics.

Nishimura Yusuke Y Bittel Adam J AJ Stead Connor A CA Chen Yi-Wen YW Burniston Jatin G JG

Molecular & cellular proteomics : MCP 20230622 8

Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight into disease mechanisms underpinned by post-transcriptional processes. We used stable isotope (deuterium oxide; D<sub>2</sub>O) labeling and peptide mass spectrometry to investigate the abundance and turnover rates of proteins in cultured muscle cells from two individuals affected by FSHD and their unaffected siblings (UASb). We measured the abundance of 4420 proteins and the turnover rate of 2324 proteins ...[more]

PMID: 37353005

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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.

			Action	DRS
	MDUK_FBS_MOE.MSMS.mgf	Mgf
	MDUK_FBS_MOE.mzid.gz	Mzid
	S10_1.raw	Raw
	S13_1.raw	Raw
	S14_1.raw	Raw