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Published on: September 16, 2019
Mouse Dux is myotoxic and shares partial functional homology with its human paralog DUX4
Jocelyn O Eidahl1, Carlee R Giesige1,2, Jacqueline S Domire1
1Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Abstract:
D4Z4 repeats are present in at least 11 different mammalian species, including humans and mice. Each repeat contains an open reading frame encoding a double homeodomain (DUX) family transcription factor. Aberrant expression of the D4Z4 ORF called DUX4 is associated with the pathogenesis of Facioscapulohumeral muscular dystrophy (FSHD). DUX4 is toxic to numerous cell types of different species, and over-expression caused dysmorphism and developmental arrest in frogs and zebrafish, embryonic lethality in transgenic mice, and lesions in mouse muscle. Because DUX4 is a primate-specific gene, questions have been raised about the biological relevance of over-expressing it in non-primate models, as DUX4 toxicity could be related to non-specific cellular stress induced by over-expressing a DUX family transcription factor in organisms that did not co-evolve its regulated transcriptional networks. We assessed toxic phenotypes of DUX family genes, including DUX4, DUX1, DUX5, DUXA, DUX4-s, Dux-bl and mouse Dux. We found that DUX proteins were not universally toxic, and only the mouse Dux gene caused similar toxic phenotypes as human DUX4. Using RNA-seq, we found that 80% of genes upregulated by Dux were similarly increased in DUX4-expressing cells. Moreover, 43% of Dux-responsive genes contained ChIP-seq binding sites for both Dux and DUX4, and both proteins had similar consensus binding site sequences. These results suggested DUX4 and Dux may regulate some common pathways, and despite diverging from a common progenitor under different selective pressures for millions of years, the two genes maintain partial functional homology.
Insights
Mouse Dux and human DUX4 proteins show functional similarity, regulating common gene pathways despite species divergence. This finding is crucial for understanding Facioscapulohumeral muscular dystrophy (FSHD) pathogenesis in non-primate models.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- The D4Z4 repeat contains a gene encoding the DUX4 transcription factor, whose aberrant expression is linked to Facioscapulohumeral muscular dystrophy (FSHD).
- DUX4 is primate-specific, raising questions about the validity of non-primate models due to potential non-specific cellular stress from overexpressed transcription factors.
Purpose of the Study:
- To investigate the toxicity and functional homology of various DUX family genes, including human DUX4 and mouse Dux, in non-primate models.
- To determine if DUX4's toxicity in non-primate models is specific or a general effect of DUX protein overexpression.
Main Methods:
- Assessed toxic phenotypes of DUX family genes (DUX4, DUX1, DUX5, DUXA, DUX4-s, Dux-bl, mouse Dux) upon overexpression.
- Utilized RNA-sequencing (RNA-seq) to compare gene expression profiles between DUX4-expressing cells and cells expressing mouse Dux.
- Employed ChIP-sequencing (ChIP-seq) to identify binding sites for Dux and DUX4 proteins.
Main Results:
- DUX proteins were not universally toxic; only mouse Dux exhibited toxic phenotypes similar to human DUX4.
- RNA-seq revealed that 80% of genes upregulated by mouse Dux were also increased in DUX4-expressing cells.
- ChIP-seq analysis showed that 43% of Dux-responsive genes contained binding sites for both Dux and DUX4, with similar consensus binding sequences.
Conclusions:
- Mouse Dux and human DUX4 share partial functional homology, regulating some common gene pathways despite millions of years of divergent evolution.
- The findings support the biological relevance of using mouse models to study DUX4 function and FSHD pathogenesis, as mouse Dux mimics key toxic effects of DUX4.
