Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction
- Fred Hutchinson Cancer Research Center, United States
- The University of Texas Southwestern Medical Center, United States
- University of Colorado Anschutz Medical Campus, United States
Abstract
DUX4 activates the first wave of zygotic gene expression in the early embryo. Mis-expression of DUX4 in skeletal muscle causes facioscapulohumeral dystrophy (FSHD), whereas expression in cancers suppresses IFNg-induction of MHC Class I and contributes to immune evasion. We show that the DUX4 protein interacts with STAT1 and broadly suppresses expression of IFNg stimulated genes by decreasing bound STAT1 and Pol-II recruitment. Transcriptional suppression of ISGs requires conserved (L)LxxL(L) motifs in the carboxyterminal region of DUX4 and phosphorylation of STAT1 Y701 enhances interaction with DUX4. Consistent with these findings, expression of endogenous DUX4 in FSHD muscle cells and the CIC-DUX4 fusion containing the DUX4 CTD in a sarcoma cell line inhibit IFNg-induction of ISGs. Mouse Dux similarly interacted with STAT1 and suppressed IFNg induction of ISGs. These findings identify an evolved role of the DUXC family in modulating immune signaling pathways with implications for development, cancers, and FSHD.
Data availability
RNA sequencing data and CUT&Tag data are available through GEO GSE186244 and GSE209785, respectively. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD029215. Standard packages were used for RNA sequencing and CUT&Tag analyses (see 'Materials & Methods'); specific code available upon request.
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RNA sequencingNCBI Gene Expression Omnibus, GSE186244.
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CUT&TagNCBI Gene Expression Omnibus, GSE209785.
Article and author information
Author details
Stephen J Tapscott
Funding
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR045203)
- Stephen J Tapscott
National Cancer Institute (P30 CA015704)
- Stephen J Tapscott
National Institutes of Health (T32 HG000035)
- Amy E Spens
Friends of FSH Research
- Stephen J Tapscott
Chris Carrino Foundation
- Stephen J Tapscott
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Spens et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction
eLife 12:e82057.
https://doi.org/10.7554/eLife.82057
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