Affinage

DUX4

Double homeobox protein 4 · UniProt Q9UBX2

Length
424 aa
Mass
44.9 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DUX4 is a double-homeodomain transcription factor that functions as a pioneer factor to drive a cleavage-stage/early embryonic gene expression program, activating germline and 2C-like genes (ZSCAN4, KDM4E, PRAMEF family) and ERVL/MaLR-class endogenous retrotransposons, with mouse Dux being necessary and sufficient to convert mESCs to a 2C-like state (PMID:28459457, PMID:22209328). Its tandem homeodomains bind DNA in a head-to-head configuration recognizing two TAAT cores separated by a spacer; a primate-specific arginine-to-glutamate substitution in the recognition helix of the second homeodomain causes the two domains to read divergent sequences, explaining species-specific retrotransposon target divergence (PMID:30540931, PMID:26823969, PMID:28459454). Transcriptional activation and cytotoxicity are separable from DNA binding and map to a C-terminal activation domain that recruits p300/CBP histone acetyltransferases and the Mediator complex (via a KIX-binding motif), driving H3K27 acetylation and chromatin opening at target loci, while the homeodomains alone suffice to inhibit MyoD-dependent myogenesis (PMID:26951377, PMID:35402882, PMID:29618456, PMID:18833193). Pathological mis-expression of DUX4 is intrinsically cytotoxic, inducing caspase-dependent apoptosis, oxidative stress sensitization, and a cascade of downstream insults: degradation of the NMD factor UPF1 (with DUX4 mRNA itself an NMD substrate, forming a stabilizing feedback loop and generating toxic truncated proteins such as SRSF3) (PMID:25564732, PMID:37314931), bidirectional transcription of HSATII pericentric satellite repeats producing cytotoxic nuclear dsRNA foci (PMID:31630170, PMID:28273136), TDP-43 aggregation linked to ubiquitin-proteasome dysfunction (PMID:25750920, PMID:23206257), and induction of muscle atrophy E3 ligases MuRF1/Atrogin1 (PMID:22053214). DUX4 also suppresses immunity by directly binding phospho-STAT1 to block IFN-γ-stimulated gene and MHC class I induction (PMID:37092726, PMID:31327741). DUX4 expression is normally restrained by NuRD/CAF-1-mediated chromatin repression at D4Z4, relieved by DUX4-induced MBD3L proteins in a feed-forward loop, and is positively driven by p38α/β MAPK signaling, a p53-binding LTR10C element, WDR5, and muscle-specific enhancers (PMID:29533181, PMID:31189728, PMID:34267371, PMID:37021550, PMID:24636994). As an oncogenic driver, DUX4 chromosomal rearrangements and fusions (DUX4-IGH, CIC-DUX4, ERG rearrangement) transform cells through neomorphic transcriptional activation of targets including ETV4, CCNE1, and ERGalt (PMID:27019113, PMID:31329165, PMID:27776115, PMID:34642317).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2007 High

    Established DUX4 as a sequence-specific transcriptional activator, defining its molecular identity as a TAAT-binding factor.

    Evidence EMSA, site-directed mutagenesis, and luciferase reporter in C2C12 cells on a Pitx1 promoter element

    PMID:17984056

    Open questions at the time
    • Whether PITX1 is a genuine direct target was later challenged
    • Genome-wide binding not addressed
  2. 2008 High

    Showed DUX4 is intrinsically cytotoxic and anti-myogenic, repressing MyoD and the glutathione redox pathway, with Pax3/Pax7 antagonism implicating homeodomain competition.

    Evidence Isogenic titratable myoblast expression system with expression profiling and Pax3/Pax7 rescue

    PMID:18833193

    Open questions at the time
    • Direct vs indirect target distinction not resolved
    • Mechanism of Pax competition not defined at the chromatin level
  3. 2010 High

    Demonstrated that myopathic activity requires DNA binding, linking the transcription-factor function directly to in vivo pathology.

    Evidence DNA-binding mutant plus p53-null cross in zebrafish and mouse muscle models

    PMID:21446026

    Open questions at the time
    • p53-dependence was later contradicted by other models
    • Identity of direct toxic target genes not established
  4. 2011 High

    Connected DUX4 to retrotransposon biology and innate immune modulation, broadening its role beyond single protein-coding targets.

    Evidence ChIP-seq, expression profiling, and reporter assays in muscle cells, including DEFB103 activation; plus atrophy ligase induction and ASO knockdown

    PMID:22053214 PMID:22209328

    Open questions at the time
    • How retrotransposon activation contributes to toxicity not yet causal
    • Mechanism of immune suppression unresolved at this stage
  5. 2012 Medium

    Characterized the rarity and intercellular spread of DUX4 protein and its ubiquitin-proteasome-regulated stability, informing the burst-like nature of expression.

    Evidence Quantitative immunodetection, nuclear scoring, and proteasome inhibitor stability assays in FSHD cells

    PMID:23206257

    Open questions at the time
    • Mechanism of nuclear diffusion unproven
    • E3 ligase mediating DUX4 turnover not identified
  6. 2014 High

    Defined tissue-specific transcriptional control via muscle enhancers and a p53-independent G1 arrest mechanism through Sp1-driven p21.

    Evidence 3C chromatin looping and ChIP for DME1/DME2 enhancers; flow cytometry, p21 reporter, Sp1 site mutation and ChIP

    PMID:24589735 PMID:24636994

    Open questions at the time
    • p21/Sp1 mechanism later shown to be mouse-specific
    • Enhancer activation triggers not fully defined
  7. 2015 High

    Uncovered NMD inhibition via UPF1 degradation as a core toxicity and feedback mechanism, and linked DUX4 to TDP-43 aggregation and proteostasis collapse.

    Evidence DUX4-inducible cell systems with RNA-seq, NMD reporters, UPF1 quantification, fractionation, and proteasome inhibition

    PMID:25564732 PMID:25750920

    Open questions at the time
    • Mechanism by which DUX4 triggers UPF1 degradation unresolved
    • Direct vs indirect cause of TDP-43 aggregation unclear
  8. 2016 High

    Mapped the molecular basis of DUX4 transcriptional activation to C-terminal recruitment of p300/CBP and its pioneer-factor behavior at MaLR chromatin, and refined its DNA-binding code.

    Evidence Mass-spec co-IP, ChIP-seq, C-terminal deletion/dominant-negative constructs; SELEX-like binding with systematic mutagenesis

    PMID:26823969 PMID:26951377

    Open questions at the time
    • Stoichiometry of p300/CBP recruitment not defined
    • Pioneer-factor nucleosome engagement mechanism not structurally resolved
  9. 2016 High

    Established the DUX4 double homeodomain as an oncogenic driver through chromosomal rearrangements producing neomorphic transcription.

    Evidence DUX4-IGH pro-B transplantation leukemia model and DUX4-driven ERGalt dominant-negative transformation assays

    PMID:27019113 PMID:27776115

    Open questions at the time
    • Full target repertoire of fusion oncoproteins incomplete
    • Relationship between FSHD and oncogenic programs not directly compared
  10. 2016 Medium

    Identified cytoplasmic and cytoskeletal/RNA-binding-protein interactions, suggesting non-nuclear roles or sequestration of DUX4/DUX4c.

    Evidence Y2H, HaloTag co-purification, GST pulldown, co-IP, and PLA identifying desmin, LMCD1, FUS, SFPQ, and others

    PMID:26816005

    Open questions at the time
    • Functional consequence of cytoplasmic interactions undefined
    • Some interactions lack reciprocal in vivo validation
  11. 2017 High

    Defined DUX4 as the master activator of zygotic/2C-like genome activation, conserved with mouse Dux but with species-divergent retrotransposon targeting.

    Evidence ATAC-seq, RNA-seq, ChIP-seq, and necessary-and-sufficient Dux KO/OE in mESCs plus cross-species expression

    PMID:28459454 PMID:28459457

    Open questions at the time
    • In vivo requirement during human embryogenesis not directly tested here
    • Basis for promoter vs retrotransposon target divergence not yet structural
  12. 2017 Medium

    Linked DUX4 toxicity to MYC induction and dsRNA innate immune activation, and dissected which domains drive cytotoxicity versus differentiation block.

    Evidence siRNA screen with RNA-seq and dsRNA/EIF4A3 imaging; homeodomain-swap and deletion constructs in C2C12

    PMID:28273136 PMID:28935672

    Open questions at the time
    • Source of dsRNA not yet identified at this stage
    • Relative contribution of each toxic pathway to cell death not quantified
  13. 2018 High

    Resolved the structural basis of tandem-homeodomain DNA recognition, explaining a primate-specific mutation driving divergent half-site specificity and a clamp-like activation mechanism.

    Evidence X-ray crystallography of the tandem and HD2 domains with mutagenesis, EMSA, and B-cell differentiation assays

    PMID:29572508 PMID:30540931

    Open questions at the time
    • Structure of full-length DUX4 with cofactors not solved
    • How DNA binding couples to p300/Mediator recruitment not structurally shown
  14. 2018 High

    Identified NuRD/CAF-1 chromatin complexes as the repressive machinery silencing D4Z4 and a MBD3L-driven feed-forward loop relieving that repression.

    Evidence CRISPR/Cas9 enChIP locus-specific proteomics of D4Z4 with siRNA functional validation

    PMID:29533181

    Open questions at the time
    • Trigger that initiates the first de-repression event unclear
    • Quantitative contribution of MBD3L feedback in vivo not defined
  15. 2019 High

    Reconciled the toxicity pathway by identifying bidirectionally transcribed HSATII satellite RNA as the causal dsRNA species driving cell death.

    Evidence RNA-seq, dsRNA imaging, and gapmer knockdown rescuing DUX4-induced death

    PMID:31630170

    Open questions at the time
    • How DUX4 initiates HSATII bidirectional transcription not mechanistically defined
    • Sensor mediating dsRNA toxicity not pinpointed
  16. 2019 Medium

    Revealed a histone-variant-based chromatin memory mechanism (H3.X/H3.Y) enabling target gene re-activation after transient DUX4 pulses.

    Evidence Doxycycline-inducible DUX4 myoblasts with CUT&RUN and pulse-chase RNA-seq plus knockdown

    PMID:31722199

    Open questions at the time
    • Deposition machinery for H3.X/H3.Y not identified
    • Persistence duration in patient cells unknown
  17. 2019 High

    Established upstream signaling control of DUX4 by p38α/β MAPK and downstream immune-evasion and metastatic programs across FSHD and cancer.

    Evidence Isoform-specific p38 siRNA and inhibitors with RNA-seq and xenografts; IFN-γ/MHC-I suppression assays; CIC-DUX4 ETV4/CCNE1 targeting; CXCR4-SDF1 migration assay

    PMID:27556182 PMID:31189728 PMID:31327741 PMID:31329165

    Open questions at the time
    • How p38 signaling intersects D4Z4 chromatin not detailed
    • Direct vs indirect immune-target relationships incompletely mapped
  18. 2020 Medium

    Challenged the earlier p53-dependence of DUX4 toxicity and demonstrated translation of toxic truncated proteins from NMD-compromised transcripts.

    Evidence p53-null mouse cross and inhibitor assays with transcriptomic meta-analysis; ribosome profiling, MS, and SRSF3-truncation gain/loss-of-function

    PMID:28754837 PMID:37314931

    Open questions at the time
    • Reconciliation of conflicting p53 results across models incomplete
    • Full set of toxic truncated proteins not catalogued
  19. 2021 High

    Defined a conserved p53-LTR10C activation axis and additional regulators (WDR5, WNT/β-catenin) controlling DUX4 expression and toxicity.

    Evidence p53 ChIP-seq and binding-site mutation across species; WDR5 proteomics/inhibitor rescue; β-catenin fractionation and WNT inhibitor rescue; CIC-DUX4 p300/CBP dependence

    PMID:34267371 PMID:34642317 PMID:36158201 PMID:37021550

    Open questions at the time
    • Integration of multiple upstream activators into a single regulatory logic unclear
    • Tissue specificity of these axes in vivo incompletely tested
  20. 2022 Medium

    Connected DUX4 to the Mediator complex and genome-wide enhancer activation within ERVL-MaLR elements during embryonic genome activation.

    Evidence ATAC-seq, CRISPR activation of enhancer regions, Mediator co-IP, and DUX4 knockdown in human zygotes

    PMID:35402882

    Open questions at the time
    • KIX-Mediator interaction interface not structurally resolved
    • Causal contribution of each enhancer to embryonic development untested
  21. 2023 High

    Defined the direct molecular mechanism of DUX4-mediated immune evasion through phospho-STAT1 binding and blockade of ISG transcription.

    Evidence Co-IP with C-terminal motif mutagenesis, IFN-γ RNA-seq, STAT1/Pol-II ChIP, across FSHD and CIC-DUX4 sarcoma cells, conserved in mouse

    PMID:37092726

    Open questions at the time
    • Stoichiometry and structure of the DUX4-STAT1 complex unknown
    • Therapeutic exploitation in tumors untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple upstream activators (p53, p38 MAPK, WDR5, NuRD/CAF-1 derepression) integrate to produce the rare, stochastic bursts of DUX4 in FSHD muscle, and which single intervention point most effectively halts the downstream toxic cascade, remains unresolved.
  • No unified model linking chromatin state, signaling, and burst kinetics
  • Relative therapeutic priority among UPF1/NMD, HSATII dsRNA, p38, and WNT axes undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 2 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-4839726 Chromatin organization 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953854 Metabolism of RNA 2
Partners
CREBBPDESEP300FUSSFPQSTAT1UPF1WDR5

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 DUX4 functions as a transcriptional activator of PITX1; it binds a specific 30-bp sequence in the Pitx1 promoter (containing a TAAT core motif) as demonstrated by EMSA, and mutations of the TAAT core abolished both DUX4 binding in vitro and Pitx1-luciferase reporter activation in C2C12 cells. Luciferase reporter assay, EMSA, site-directed mutagenesis, transfection in C2C12 cells Proceedings of the National Academy of Sciences of the United States of America High 17984056
2007 DUX4 localizes to the nucleus and its overexpression induces caspase 3/7-dependent apoptosis and alters emerin distribution at the nuclear envelope. CMV-DUX4 transfection, caspase 3/7 activity assay, immunofluorescence localization, nuclear fractionation Neuromuscular disorders : NMD Medium 17588759
2008 DUX4 expression represses MyoD and its target genes, diminishes myogenic differentiation, represses glutathione redox pathway components, and sensitizes cells to oxidative stress; DUX4 toxicity is antagonized by high-level expression of Pax3 or Pax7, suggesting competitive interaction via related homeodomains. Inducible cassette exchange isogenic myoblast expression screen, gene expression profiling, Pax3/Pax7 co-expression rescue experiments The EMBO journal High 18833193
2010 DUX4 myopathic activity in vivo requires intact DNA binding (a DNA-binding domain mutant caused no muscle abnormalities), and DUX4-induced myopathy in mice is p53-dependent (p53-null muscles are resistant to DUX4-induced damage). Transposon-mediated transgenesis in zebrafish, AAV delivery in mouse muscle, DNA-binding domain mutant, p53-null mouse cross Annals of neurology High 21446026
2011 DUX4 activates germline and early stem cell genes, binds and activates LTR elements from MaLR endogenous primate retrotransposons, and suppresses the innate immune response to viral infection at least partly through activation of DEFB103 (a human defensin that can inhibit muscle differentiation). ChIP-seq, gene expression profiling, reporter assays, DUX4 transfection in muscle cells Developmental cell High 22209328
2011 DUX4 expression in myoblasts induces atrophic myotube formation associated with induction of E3 ubiquitin ligases MuRF1 and Atrogin1/MAFbx; siRNA and antisense oligonucleotides targeting DUX4 mRNA suppressed DUX4 protein and reduced downstream target expression in FSHD myoblasts. DUX4 expression vector transfection, siRNA/antisense knockdown, qRT-PCR, immunofluorescence PloS one Medium 22053214
2012 DUX4 protein is expressed in only ~1/1000 FSHD myoblasts but ~1/200 myotube nuclei; DUX4 and its target PITX1 show protein staining gradients across consecutive myonuclei suggesting diffusion between nuclei; both protein half-lives are regulated by the ubiquitin-proteasome pathway. Immunodetection, quantitative nuclear scoring, proteasome inhibitor treatment, protein stability assays Journal of cellular and molecular medicine Medium 23206257
2014 DUX4 induces G1 cell cycle arrest by upregulating p21 expression in a p53-independent manner via increased Sp1 transcription factor binding to the p21 promoter; ChIP confirmed DUX4-induced Sp1 binding to the p21 promoter in vivo. Cell cycle analysis (flow cytometry), p21 promoter-luciferase reporter, Sp1 binding site mutation, ChIP assay, p21 siRNA rescue Biochemical and biophysical research communications Medium 24589735
2014 DUX4 expression is driven by two muscle-specific enhancers (DME1 and DME2) that physically interact with the DUX4 promoter in skeletal myocytes (confirmed by chromosome conformation capture) but not in fibroblasts, explaining muscle-tissue specificity of DUX4-fl expression. Chromatin immunoprecipitation (ChIP), chromosome conformation capture (3C), nucleosome occupancy and methylome sequencing, luciferase reporters Molecular and cellular biology High 24636994
2015 DUX4 protein triggers proteolytic degradation of UPF1, a central NMD component, causing profound NMD inhibition and global accumulation of NMD substrate RNAs; DUX4 mRNA is itself an NMD substrate, creating a double-negative feedback loop that stabilizes DUX4 mRNA. DUX4-inducible cell system, RNA-seq, UPF1 protein quantification, NMD reporter assays eLife High 25564732
2015 DUX4-FL expression inhibits protein turnover via the ubiquitin-proteasome system and induces TDP-43 aggregation in expressing nuclei; the non-toxic short isoform DUX4-S does not cause these changes. Proteasome inhibition with MG132 phenocopies TDP-43 aggregation. Exogenous BacMam DUX4-FL expression, immunofluorescence, insoluble protein fractionation, proteasome inhibitor treatment Annals of clinical and translational neurology Medium 25750920
2016 DUX4 recruits the histone acetyltransferases p300/CBP through its C-terminus (identified by mass spectrometry); C-terminal deleted DUX4 cannot recruit p300 or induce H3K27Ac at target loci. DUX4 acts as a pioneer factor at inaccessible H3K27Ac-depleted MaLR-enriched chromatin, recruiting H3K27 acetyltransferase activity and opening loci for transcription, while simultaneously depleting H3K27Ac at distant strong peaks. Mass spectrometry co-IP, ChIP-seq (DUX4, H3, H3K27Ac, H3K4me3), C-terminal deletion and dominant-negative constructs, inducible DUX4 myoblast system Nucleic acids research High 26951377
2016 The DUX4 double homeodomain has a defined DNA-binding consensus with two tandem TAAT motifs separated by a C residue; a single TAAT half-site has no transcriptional activity; DUX4 does not bind the TAATTA motif in the Pitx1 promoter, challenging PITX1 as a direct DUX4 target gene. Transcriptional activation shows strong synergy with multiple binding sites. SELEX-like unbiased binding assays, electrophoretic mobility shift assay (EMSA), luciferase reporter assay with systematic mutagenesis Skeletal muscle High 26823969
2016 DUX4 and DUX4c interact with type III intermediate filament protein desmin in the cytoplasm and at the nuclear periphery, and with Z-disc protein LMCD1; they also interact with RNA-binding proteins C1QBP, SRSF9, RBM3, FUS/TLS, and SFPQ. DUX4/DUX4c are detected in the cytoplasm upon myoblast fusion and associate with nuclear buds. Yeast two-hybrid, HaloTag co-purification, GST pull-down, co-immunoprecipitation, co-immunofluorescence, proximity ligation assay (PLA) PloS one Medium 26816005
2016 DUX4-IGH fusion expression in mouse pro-B cells generates B cell leukemia in vivo (transplantation assay), demonstrating that the DUX4 double homeodomain can act as an oncogenic driver when overexpressed due to chromosomal rearrangement. RNA-seq, transplantation assay in mice (pro-B cell transformation), RT-PCR Nature genetics High 27019113
2016 DUX4 rearrangement drives expression of ERGalt, a non-canonical ERG isoform, by binding to a DUX4-Responsive-Element (DRE) in a non-canonical first exon; ERGalt retains DNA-binding and transactivation domains but acts as a dominant-negative inhibitor of wild-type ERG and is transforming. RNA-seq, ChIP, reporter assays, ERGalt expression constructs, transformation assays Nature genetics High 27776115
2017 DUX4 and mouse DUX activate hundreds of cleavage-stage genes (e.g., ZSCAN4, KDM4E, PRAMEF-family) and MERVL/HERVL retrotransposons; mouse Dux expression is necessary and sufficient to convert mESCs into 2C-like cells (reactivation of 2C genes, loss of OCT4 protein/chromocenters, remodeling of chromatin to 2C state). ATAC-seq, RNA-seq, Dux overexpression and knockdown in mESCs, ChIP-seq, immunofluorescence Nature genetics High 28459457
2017 Despite divergent binding motifs, human DUX4 and mouse DUX both activate cleavage-stage genes driven by conventional promoters in their respective species; retrotransposon-driven gene activation diverges between species correlating with homeodomain sequence divergence. Human DUX4 expressed in mouse cells does not activate MERVL-promoted genes. RNA-seq, ChIP-seq, cross-species expression experiments (human DUX4 in mouse cells), motif analysis Nature genetics High 28459454
2017 DUX4 expression causes accumulation of MYC mRNA, nuclear double-stranded RNA (dsRNA) foci with EIF4A3 aggregation, and activation of the dsRNA innate immune response pathway; siRNA screen identified MYC-mediated apoptotic pathway and dsRNA response as mediators of DUX4-induced apoptosis. siRNA screen (RD rhabdomyosarcoma inducible DUX4), RNA-seq, immunofluorescence for dsRNA foci and EIF4A3, MYC mRNA quantification PLoS genetics Medium 28273136
2017 CIC-DUX4 fusion oncoprotein directly and neomorphically upregulates ETV4 and CCNE1 (cyclin E1), driving tumor metastasis and survival respectively; CCNE-CDK2 complex dependence renders CIC-DUX4 tumors sensitive to CDK2 inhibition. Gene silencing, gene expression profiling, xenograft mouse models, CIC-DUX4 transgenic mouse model (embryonic mesenchymal cells), CDK inhibitor treatment The Journal of clinical investigation High 31329165
2018 Crystal structure of the tandem DUX4 homeodomains bound to DNA reveals head-to-head binding with linker making minor-groove contacts; despite being tandem duplicates, the two homeodomains recognize different core sequences due to a primate-specific arginine-to-glutamate mutation in the recognition helix of HD2. Mutational studies confirmed this primate-specific change drives divergent sequence recognition. X-ray crystallography, mutagenesis (alanine substitutions and R-to-E reversion), electrophoretic mobility shift assay Cell reports High 30540931
2018 Crystal structure of the DUX4 second homeodomain (HD2) in apo and DNA-bound forms reveals a clamp-like transactivation mechanism; mutations in the DNA-binding interfaces impaired DUX4 DNA-binding affinity and abrogated DUX4/IGH transactivation activity and inhibitory effects on B-cell differentiation. X-ray crystallography (apo and DNA-bound structures), biophysical binding assays, mutagenesis, B-cell differentiation assay in mouse progenitors Leukemia High 29572508
2018 DUX4 functional domains were mapped: homeodomains are required for inhibiting myogenesis and MyoD expression but do not require the C-terminal activation domain; the C-terminal ~80 amino acids (especially the last 20) mediate transcriptional activation and cytotoxicity. Non-toxic homeodomain-containing constructs lacking the C-terminus can act as inhibitors of DUX4-FL by competing for promoter sites. DUX4 deletion/mutation/fusion constructs, DUX4 promoter reporter assay, ZSCAN4 expression, cell viability assay, caspase activation assay, ubiquitination assay Biology open Medium 29618456
2018 The NuRD (Nucleosome Remodeling Deacetylase) and CAF-1 (Chromatin Assembly Factor 1) complexes are necessary for DUX4 repression in human skeletal muscle cells and iPSCs; DUX4-induced MBD3L proteins partly relieve this repression in FSHD muscle cells, providing a positive feedback mechanism for DUX4 amplification. CRISPR/Cas9-based enChIP locus-specific proteomics of D4Z4, siRNA knockdown of NuRD/CAF-1 components, DUX4 expression assays eLife High 29533181
2019 DUX4 expression blocks interferon-γ-mediated induction of MHC class I gene expression, enabling immune evasion; re-expression of DUX4 in diverse cancers is associated with reduced cytolytic activity markers and lower MHC class I expression. IFN-γ stimulation assays with DUX4-expressing vs. control cancer cells, RNA-seq, clinical melanoma data correlation Developmental cell Medium 31327741
2019 DUX4-induced dsRNA foci are composed primarily of bidirectionally transcribed HSATII (human satellite II) pericentric repeat RNAs; DUX4 initiates bidirectional transcription of normally silenced HSATII repeats, and gapmer-mediated knockdown of HSATII transcripts depletes nuclear ribonucleoprotein aggregates and decreases DUX4-induced cell death. RNA-seq, immunofluorescence for dsRNA foci, gapmer antisense knockdown, co-localization of HSATII RNA with EIF4A3 and ADAR1 Human molecular genetics High 31630170
2019 DUX4-induced histone variants H3.X and H3.Y are incorporated throughout the body of DUX4-induced genes; following a brief DUX4 pulse, these histones contribute to greater perdurance and enhanced re-activation of DUX4 target gene expression, providing a chromatin memory mechanism. Doxycycline-inducible DUX4 myoblasts, CUT&RUN for H3.X/H3.Y, RNA-seq after DUX4 pulse, H3.X/H3.Y knockdown experiments Cell reports Medium 31722199
2019 p38α and p38β MAPK isoforms each independently and requisitely regulate DUX4 expression; pharmacological inhibition of p38α/β suppresses DUX4 mRNA expression and downstream target gene program in FSHD myoblasts and in mouse xenografts, as confirmed by RNA-seq profiling. siRNA knockdown of individual p38 isoforms, multiple selective p38α/β inhibitors, RNA-seq, FSHD1 and FSHD2 patient cells, xenograft model The Journal of pharmacology and experimental therapeutics High 31189728
2020 DUX4 expression in FSHD muscles leads to compromised NMD which results in translation of truncated proteins from NMD-targeted transcripts; RNA-binding proteins are enriched for aberrant truncations, and the truncated SRSF3 isoform is translated to a stable protein that itself confers toxicity—its downregulation is cytoprotective. Cell-based FSHD model (DUX4 induction), ribosome profiling, mass spectrometry, SRSF3 truncation construct expression, siRNA knockdown of truncated SRSF3, FSHD patient-derived myotube validation Cell reports High 37314931
2021 p53 activates DUX4/Dux expression via a p53-binding site located in a primate-specific subtelomeric LTR10C element; the p53–DUX4 regulatory axis is conserved between mouse Dux and human DUX4, and this pathway operates in FSHD patient cells during p53 signaling. Long-read sequencing of Dux locus, CHIP-seq for p53 binding, DUX4/Dux induction upon p53 activation, p53 binding site mutation, FSHD patient-derived cell experiments Nature genetics High 34267371
2021 WDR5, a chromatin remodeling protein, is a direct interactor of the lncRNA DBE-T and is required for DUX4 expression and target gene activation in FSHD primary muscle cells; pharmacological WDR5 inhibition rescues cell viability and myogenic differentiation in FSHD patient cells. Affinity purification followed by proteomics, WDR5 siRNA knockdown, WDR5 pharmacological inhibitor, DUX4 and target gene expression assays, myogenic differentiation assay, viability assay Nucleic acids research High 37021550
2021 DUX4 promotes nuclear translocation of β-CATENIN and increases canonical WNT signalling; constitutive DUX4c expression prevents β-CATENIN nuclear accumulation and the downstream transcriptional program; blockade of WNT/β-CATENIN signalling rescues viability of FSHD myoblasts. DUX4 and DUX4c expression constructs, β-catenin nuclear fractionation/immunofluorescence, WNT pathway inhibitor treatment, cell viability assay, FSHD myoblast rescue Frontiers in cell and developmental biology Medium 36158201
2022 DUX4 interacts with the Mediator complex via a C-terminal KIX binding motif; DUX4 expression substantially alters chromatin accessibility (ATAC-seq) and activates thousands of transcribed enhancer-like regions preferentially within ERVL-MaLR repeat elements; CRISPR activation of these enhancer regions via C-terminal DUX4 motifs increases expression of EGA genes ZSCAN4 and KHDC1P1. ATAC-seq, CRISPR activation, DUX4 knockdown in human zygotes (transcriptome analysis), immunofluorescence in zygotes, protein co-IP/interaction for Mediator complex iScience Medium 35402882
2023 DUX4 protein directly interacts with STAT1 via conserved (L)LxxL(L) motifs in its C-terminal region, and this interaction requires STAT1 Y701 phosphorylation; DUX4 broadly suppresses IFN-γ-stimulated gene expression by decreasing STAT1 and Pol-II recruitment at ISG promoters. This mechanism is conserved (mouse Dux also interacts with STAT1), and operates in FSHD muscle cells and CIC-DUX4 sarcoma. Co-IP (DUX4-STAT1 interaction), C-terminal motif mutagenesis, RNA-seq after IFN-γ stimulation ± DUX4, ChIP for STAT1 and Pol-II at ISG promoters, FSHD patient cell validation, sarcoma cell line validation eLife High 37092726
2021 CIC-DUX4 fusion requires P300/CBP to induce histone H3 acetylation and activate its transcriptional targets; pharmacological P300/CBP inhibition (iP300w) suppresses CIC-DUX4 transcriptional activity, reverses induced H3 acetylation, induces cell cycle arrest in CDS cell lines, and prevents growth of CDS xenograft tumors in vivo. P300/CBP inhibitor treatment, H3 acetylation ChIP, transcriptional reporter assays, xenograft mouse model, cell viability assay Oncogenesis High 34642317
2016 DUX4 controls CXCR4 and CXCL12/SDF1 expression in myoblasts; DUX4 overexpression increases mesenchymal stem cell migration in a Transwell assay, and this effect is blocked by antibodies against SDF1 and CXCR4, placing DUX4 upstream of the CXCR4-SDF1 axis in regulating cell migration. Transcriptome profiling (microarray), Transwell migration assay, antibody blocking, DUX4 overexpression in myoblasts and BMSCs Oncotarget Medium 27556182
2017 DUX4 homeodomains are necessary and sufficient for inhibition of myogenesis and induction of cytotoxicity; substitution mutants in which both DUX4 homeodomains are replaced by Pax7 homeodomains retain the ability to inhibit differentiation and induce cytotoxicity. Among related homeodomain proteins, only Pax3 and Pax7 (not Pax6, Pitx2c, OTX1, Rax, Hesx1, MIXL1, Tbx1) display phenotypic competition with DUX4, requiring the paired and transcriptional activation domains of Pax3 in addition to its homeodomain. Expression of homeodomain swap and deletion constructs, C2C12 differentiation assays, cytotoxicity assay, domain analysis Journal of cell science Medium 28935672
2020 DUX4-induced toxicity in C2C12 myoblasts and in the inducible mouse model is not p53-dependent: p53 inhibition has no effect on DUX4 cytotoxicity; DUX4 does not activate the canonical p53 pathway; p21/Cdkn1a induction by DUX4 is mouse-specific and p53-independent. The DUX4 inducible mouse crossed onto p53-null background shows no suppression of male-specific lethality or skin phenotypes. C2C12 cytotoxicity assay with p53 inhibitor, meta-analysis of 5 DUX4 transcriptional datasets, p53-null mouse cross with inducible DUX4 transgene, primary myoblast killing assay Disease models & mechanisms Medium 28754837
2013 NFE2L3 functions as a regulator that links NF-κB/RELA signaling to CDK1 activity via DUX4; NFE2L3 knockdown results in increased DUX4 levels, and DUX4 functions as a direct inhibitor of CDK1, thereby controlling cell cycle progression in colon cancer cells. NFE2L3 siRNA knockdown, DUX4 expression measurement, CDK1 activity assays, cell proliferation assay in vitro, tumor growth in vivo Cell reports Medium 31693889

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nature genetics 589 28459457
2011 DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Developmental cell 372 22209328
2007 DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Proceedings of the National Academy of Sciences of the United States of America 298 17984056
2007 The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein. Neuromuscular disorders : NMD 268 17588759
2017 Conservation and innovation in the DUX4-family gene network. Nature genetics 265 28459454
2008 An isogenetic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies. The EMBO journal 261 18833193
2016 Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia. Nature communications 258 27265895
2016 Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Nature genetics 251 27776115
2016 Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults. Nature genetics 232 27019113
2010 DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo. Annals of neurology 198 21446026
2016 DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes. Nucleic acids research 156 26951377
2011 The FSHD atrophic myotube phenotype is caused by DUX4 expression. PloS one 150 22053214
2012 DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy? Journal of cellular and molecular medicine 126 23206257
2011 Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends in molecular medicine 120 21288772
2015 A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy. eLife 105 25564732
2019 DUX4 Suppresses MHC Class I to Promote Cancer Immune Evasion and Resistance to Checkpoint Blockade. Developmental cell 100 31327741
2016 Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells. Human molecular genetics 94 28171552
2017 CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma. Cancer research 93 28404587
2016 Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. Molecular therapy : the journal of the American Society of Gene Therapy 93 27378237
2017 Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model. Nature communications 89 28916757
2013 Wnt/β-catenin signaling suppresses DUX4 expression and prevents apoptosis of FSHD muscle cells. Human molecular genetics 89 23821646
2021 p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models. Nature genetics 84 34267371
2017 Histological and immunohistochemical characteristics of undifferentiated small round cell sarcomas associated with CIC-DUX4 and BCOR-CCNB3 fusion genes. Virchows Archiv : an international journal of pathology 83 28197724
2016 DUX4-induced constitutive DNA damage and oxidative stress contribute to aberrant differentiation of myoblasts from FSHD patients. Free radical biology & medicine 83 27519269
2017 DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy. PLoS genetics 76 28273136
2019 NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor. Cell reports 72 31693889
2017 DUX4 Immunohistochemistry Is a Highly Sensitive and Specific Marker for CIC-DUX4 Fusion-positive Round Cell Tumor. The American journal of surgical pathology 72 27879517
2018 A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy. PloS one 71 29415061
2016 DUX4 induces a transcriptome more characteristic of a less-differentiated cell state and inhibits myogenesis. Journal of cell science 69 27744317
2019 Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy. The Journal of pharmacology and experimental therapeutics 68 31189728
2018 AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD. JCI insight 66 30429376
2013 DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles. Human molecular genetics 65 23966205
2014 Myogenic enhancers regulate expression of the facioscapulohumeral muscular dystrophy-associated DUX4 gene. Molecular and cellular biology 59 24636994
2012 Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. Human molecular genetics 59 23108159
2020 Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing mice. The Journal of clinical investigation 58 32250341
2015 Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4. Epigenetics 58 26575099
2013 DUX4 differentially regulates transcriptomes of human rhabdomyosarcoma and mouse C2C12 cells. PloS one 58 23717650
2019 CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs. The Journal of clinical investigation 57 31329165
2021 Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7. EMBO molecular medicine 56 34151531
2017 Generation of novel patient-derived CIC- DUX4 sarcoma xenografts and cell lines. Scientific reports 54 28680140
2020 DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy. International journal of molecular sciences 53 31979100
2021 DUX4 Role in Normal Physiology and in FSHD Muscular Dystrophy. Cells 52 34943834
2015 Expression of FSHD-related DUX4-FL alters proteostasis and induces TDP-43 aggregation. Annals of clinical and translational neurology 51 25750920
2018 NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins. eLife 50 29533181
2015 High-grade undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: emerging entities of soft tissue tumors with unique histopathologic features--a case report and literature review. The American journal of case reports 50 25683183
2017 The DUX4 homeodomains mediate inhibition of myogenesis and are functionally exchangeable with the Pax7 homeodomain. Journal of cell science 49 28935672
2020 Establishment and characterization of NCC-CDS2-C1: a novel patient-derived cell line of CIC-DUX4 sarcoma. Human cell 46 31898195
2015 β-Catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy. Journal of the Royal Society, Interface 46 25551153
2020 Targeted epigenetic repression by CRISPR/dSaCas9 suppresses pathogenic DUX4-fl expression in FSHD. Molecular therapy. Methods & clinical development 45 33511244
2019 PAX7 target gene repression is a superior FSHD biomarker than DUX4 target gene activation, associating with pathological severity and identifying FSHD at the single-cell level. Human molecular genetics 45 31067297
2020 Inhibition of DUX4 expression with antisense LNA gapmers as a therapy for facioscapulohumeral muscular dystrophy. Proceedings of the National Academy of Sciences of the United States of America 44 32601200
2019 DUX4-Induced Histone Variants H3.X and H3.Y Mark DUX4 Target Genes for Expression. Cell reports 44 31722199
2014 Dux4 induces cell cycle arrest at G1 phase through upregulation of p21 expression. Biochemical and biophysical research communications 44 24589735
2021 Distinct clinical characteristics of DUX4- and PAX5-altered childhood B-lymphoblastic leukemia. Blood advances 40 34547766
2021 Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy. Nature communications 40 34880230
2022 DUX4 is a multifunctional factor priming human embryonic genome activation. iScience 38 35402882
2021 Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma. Oncogenesis 38 34642317
2020 p38α Regulates Expression of DUX4 in a Model of Facioscapulohumeral Muscular Dystrophy. The Journal of pharmacology and experimental therapeutics 35 32576599
2019 DUX4-induced bidirectional HSATII satellite repeat transcripts form intranuclear double-stranded RNA foci in human cell models of FSHD. Human molecular genetics 35 31630170
2019 Undifferentiated round cell sarcomas with CIC-DUX4 gene fusion: expanding the clinical spectrum. Pathology 33 31870501
2018 Sporadic DUX4 expression in FSHD myocytes is associated with incomplete repression by the PRC2 complex and gain of H3K9 acetylation on the contracted D4Z4 allele. Epigenetics & chromatin 33 30122154
2016 Homologous Transcription Factors DUX4 and DUX4c Associate with Cytoplasmic Proteins during Muscle Differentiation. PloS one 32 26816005
2021 ETV4 and ETV5 drive synovial sarcoma through cell cycle and DUX4 embryonic pathway control. The Journal of clinical investigation 30 33983905
2018 Functional domains of the FSHD-associated DUX4 protein. Biology open 30 29618456
2016 DNA-binding sequence specificity of DUX4. Skeletal muscle 30 26823969
2020 Therapeutic Strategies Targeting DUX4 in FSHD. Journal of clinical medicine 29 32906621
2018 Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA. Cell reports 28 30540931
2016 A complex interplay of genetic and epigenetic events leads to abnormal expression of the DUX4 gene in facioscapulohumeral muscular dystrophy. Neuromuscular disorders : NMD 28 27816329
2015 Loss of epigenetic silencing of the DUX4 transcription factor gene in facioscapulohumeral muscular dystrophy. Human molecular genetics 28 26113644
2022 Integrated Molecular Characterization of Patient-Derived Models Reveals Therapeutic Strategies for Treating CIC-DUX4 Sarcoma. Cancer research 26 34903601
2021 Chromosome 10q-linked FSHD identifies DUX4 as principal disease gene. Journal of medical genetics 26 33436523
2021 Systemic antisense therapeutics inhibiting DUX4 expression ameliorates FSHD-like pathology in an FSHD mouse model. Human molecular genetics 26 33987655
2021 CRISPR mediated targeting of DUX4 distal regulatory element represses DUX4 target genes dysregulated in Facioscapulohumeral muscular dystrophy. Scientific reports 26 34131248
2020 Designed U7 snRNAs inhibit DUX4 expression and improve FSHD-associated outcomes in DUX4 overexpressing cells and FSHD patient myotubes. Molecular therapy. Nucleic acids 26 33510937
2017 p53-independent DUX4 pathology in cell and animal models of facioscapulohumeral muscular dystrophy. Disease models & mechanisms 26 28754837
2022 Transient DUX4 expression in human embryonic stem cells induces blastomere-like expression program that is marked by SLC34A2. Stem cell reports 25 35777358
2021 Systemic delivery of a DUX4-targeting antisense oligonucleotide to treat facioscapulohumeral muscular dystrophy. Molecular therapy. Nucleic acids 25 34729250
2020 DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 32020675
2020 Imaging features and clinical course of undifferentiated round cell sarcomas with CIC-DUX4 and BCOR-CCNB3 translocations. Skeletal radiology 25 32840647
2020 DUX Hunting-Clinical Features and Diagnostic Challenges Associated with DUX4-Rearranged Leukaemia. Cancers 25 33007870
2020 DUX4 Transcript Knockdown with Antisense 2'-O-Methoxyethyl Gapmers for the Treatment of Facioscapulohumeral Muscular Dystrophy. Molecular therapy : the journal of the American Society of Gene Therapy 25 33068777
2019 Long-read sequencing unveils IGH-DUX4 translocation into the silenced IGH allele in B-cell acute lymphoblastic leukemia. Nature communications 25 31243274
2018 Structural basis of DUX4/IGH-driven transactivation. Leukemia 25 29572508
2023 Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression. Cell reports 23 37314931
2021 Identification of candidate miRNA biomarkers for facioscapulohumeral muscular dystrophy using DUX4-based mouse models. Disease models & mechanisms 22 34338285
2020 G-quadruplex ligands mediate downregulation of DUX4 expression. Nucleic acids research 22 32182342
2023 WDR5 is required for DUX4 expression and its pathological effects in FSHD muscular dystrophy. Nucleic acids research 21 37021550
2021 Nanopore direct RNA sequencing detects DUX4-activated repeats and isoforms in human muscle cells. Human molecular genetics 21 33693705
2016 Dux4 controls migration of mesenchymal stem cells through the Cxcr4-Sdf1 axis. Oncotarget 21 27556182
2016 Nuclear bodies reorganize during myogenesis in vitro and are differentially disrupted by expression of FSHD-associated DUX4. Skeletal muscle 21 27906075
2022 Central nervous system sarcoma with ATXN1::DUX4 fusion expands the concept of CIC-rearranged sarcoma. Genes, chromosomes & cancer 20 35715887
2015 Culture Conditions Affect Expression of DUX4 in FSHD Myoblasts. Molecules (Basel, Switzerland) 20 26007167
2023 Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction. eLife 18 37092726
2023 DUX4 expression in cancer induces a metastable early embryonic totipotent program. Cell reports 18 37691147
2021 The CAM Model for CIC-DUX4 Sarcoma and Its Potential Use for Precision Medicine. Cells 18 34685592
2024 Nuclear DUX4 immunohistochemistry is a highly sensitive and specific marker for the presence of CIC::DUX4 fusion in CIC-rearranged sarcomas: a study of 48 molecularly confirmed cases. Histopathology 17 39381843
2022 WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma. JCI insight 17 35315355
2022 Antagonism Between DUX4 and DUX4c Highlights a Pathomechanism Operating Through β-Catenin in Facioscapulohumeral Muscular Dystrophy. Frontiers in cell and developmental biology 17 36158201
2020 DUX4 Expression in FSHD Muscles: Focus on Its mRNA Regulation. Journal of personalized medicine 16 32731450
2020 Gene Editing Targeting the DUX4 Polyadenylation Signal: A Therapy for FSHD? Journal of personalized medicine 16 33374516

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