{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q9UBX2","secondaryAccessions":["E2JJS1"],"uniProtkbId":"DUX4_HUMAN","entryAudit":{"firstPublicDate":"2006-10-17","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2001-10-01","entryVersion":179,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:50800"}],"value":"Double homeobox protein 4"}},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000312","source":"EMBL","id":"AAK91509.1"}],"value":"Double homeobox protein 10"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:50800"}],"value":"DUX4"},"synonyms":[{"value":"DUX10"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17984056"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"24145033"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26951377"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27378237"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28459454"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28459457"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28935672"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29572508"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29618456"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30315230"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30540931"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"36158201"}],"value":"Transcription factor that is selectively and transiently expressed in cleavage-stage embryos (PubMed:28459457). Binds to double-stranded DNA elements with the consensus sequence 5'-TAATCTAATCA-3' (PubMed:28459454, PubMed:28459457, PubMed:29572508, PubMed:30315230, PubMed:30540931). Binds to chromatin containing histone H3 acetylated at 'Lys-27' (H3K27ac) and promotes deacetylation of H3K27ac. In parallel, binds to chromatin that lacks histone H3 acetylation at 'Lys-27' (H3K27ac) and recruits EP300 and CREBBP to promote acetylation of histone H3 at 'Lys-27' at new sites (PubMed:26951377). Involved in transcriptional regulation of numerous genes, primarily as transcriptional activator, but also mediates repression of a set of target genes (PubMed:17984056, PubMed:26951377, PubMed:27378237, PubMed:28459454, PubMed:28459457, PubMed:29572508, PubMed:29618456, PubMed:30540931). Promotes expression of ZSCAN4 and KDM4E, two proteins with essential roles during early embryogenesis (PubMed:26951377, PubMed:27378237, PubMed:28459457, PubMed:29618456). Promotes nuclear translocation of CTNNB1/beta-catenin and its subsequent activation of target genes (PubMed:36158201). Heterologous expression in cultured embryonic stem cells mediates transcription of HERVL retrotransposons and transcripts derived from ACRO1 and HSATII satellite repeats (PubMed:28459457). May activate expression of PITX1 (PubMed:17984056). May regulate microRNA (miRNA) expression (PubMed:24145033). Inappropriate expression can inhibit myogenesis and promote apoptosis (PubMed:26951377, PubMed:28935672, PubMed:29618456)"}],"commentType":"FUNCTION","molecule":"Isoform 1"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29618456"}],"value":"Probably inactive as a transcriptional activator, due to the absence of the C-terminal region that is important for transcriptional activation. Can inhibit transcriptional activation mediated by isoform 1. Heterologous expression of isoform 2 has no deleterious effect on cell survival"}],"commentType":"FUNCTION","molecule":"Isoform 2"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26951377"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30322619"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30540931"}],"value":"Binds DNA as a monomer (PubMed:30322619, PubMed:30540931). Interacts (via C-terminus) with EP300 and CREBBP (PubMed:26951377)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"Q9UBX2","intActId":"EBI-11600078"},"interactantTwo":{"uniProtKBAccession":"P17661","geneName":"DES","intActId":"EBI-1055572"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"Q9UBX2","intActId":"EBI-11600078"},"interactantTwo":{"uniProtKBAccession":"P31001","geneName":"Des","intActId":"EBI-298565"},"numberOfExperiments":2,"organismDiffer":true}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Isoform 1","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"15709750"}],"value":"Actively transported through the nuclear pore complex (NPC)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00108"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15709750"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17984056"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21060811"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26816005"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26951377"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27378237"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28459457"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29618456"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26816005"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"commentType":"SUBCELLULAR LOCATION","molecule":"Isoform 2","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29618456"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"15709750"}],"value":"Nucleus","id":"SL-0191"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"21060811"}],"value":"DUX4-fl"}],"isoformIds":["Q9UBX2-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"21060811"}],"value":"DUX4-s"}],"isoformIds":["Q9UBX2-2"],"sequenceIds":["VSP_060075","VSP_060076"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17984056"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21060811"}],"value":"Isoform 1: Does not seem to be expressed in normal muscle, but is detected in muscle of individuals with FSHD, and also in testis (at protein level) (PubMed:17984056, PubMed:21060811). Isoform 1: Does not seem to be expressed in normal muscle, but in muscle of individuals with FSHD, where it may be toxic to cells (PubMed:17984056, PubMed:21060811). Isoform 2: Detected in skeletal muscle, fibroblasts and testis from healthy individuals (PubMed:21060811)"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21060811"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28459457"}],"value":"Isoform 1: Detected in embryos at the 4-cell stage. Not detected in embryos at the 2-cell stage, or at the 8-cell stage (at protein level). Detected in embryos at the 4-cell stage. Not detected in embryos at the 2-cell stage, or at the 8-cell stage (PubMed:28459457). Detected in induced pluripotent (iPS) cells, but expression is suppressed upon differentiation to embryoid bodies. Isoform 2: Detected in embryoid bodies derived from induced pluripotent (iPS) cells, but not in the induced pluripotent (iPS) cells themselves (PubMed:21060811)"}],"commentType":"DEVELOPMENTAL STAGE"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15709750"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30322619"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30540931"}],"value":"The two homeobox domains are arranged in a head-to-head orientation when bound to double-stranded DNA, each domain binding to one of the two DNA strands. Together, the homeobox domains can be considered to bind DNA with the consensus sequence 5'-TAATCTAATCA-3', but due to the head-to-head orientation of the DNA-bound domains, the first homeobox domain binds to the consensus sequence 5'-TAAT-3', and the second homeobox domain binds DNA on the opposite strand, with the consensus sequence 5'-TGAT-3' (PubMed:30322619, PubMed:30540931). Both homeobox domains confer nuclear targeting (PubMed:15709750)"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26951377"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29618456"}],"value":"The C-terminal region is required for efficient activation of transcription from target promoters (PubMed:26951377, PubMed:29618456). It mediates interaction with EP300 and CREBBP (PubMed:26951377)"}],"commentType":"DOMAIN"},{"commentType":"DISEASE","disease":{"diseaseId":"Facioscapulohumeral muscular dystrophy 1","diseaseAccession":"DI-01545","acronym":"FSHD1","description":"A degenerative muscle disease characterized by slowly progressive weakness of the muscles of the face, upper-arm, and shoulder girdle. The onset of symptoms usually occurs in the first or second decade of life. Affected individuals usually present with impairment of upper extremity elevation. This tends to be followed by facial weakness, primarily involving the orbicularis oris and orbicularis oculi muscles.","diseaseCrossReference":{"database":"MIM","id":"158900"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10433963"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19320656"}]},"note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19320656"}],"value":"The gene represented in this entry is involved in disease pathogenesis. The disease is caused by deletion of an integral number of units of a 3.3-kb tandem repeats, termed D4Z4 macrosatellite, located on chromosome 4q35. In unaffected subjects, the D4Z4 array consists of 11-150 repeats, while in FSHD1 patients, the array is reduced to 1-10 repeats (PubMed:19320656). DUX4 is located in D4Z4 macrosatellite which is epigenetically repressed in somatic tissues. D4Z4 chromatin relaxation in FSHD1 results in inefficient epigenetic repression of DUX4 and a variegated pattern of DUX4 protein expression in a subset of skeletal muscle nuclei. Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10433963"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17984056"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"19320656"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21060811"}],"value":"DUX genes are present in 3.3-kilobase elements, a tandem repeat family scattered in the genome found on the short arms of all acrocentric chromosomes as well as on several other chromosomes"}],"commentType":"MISCELLANEOUS"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the paired homeobox family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":424,"modifier":"EXACT"}},"description":"Double homeobox protein 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