DUX4
Identifiers
Aliases	DUX4, DUX4L, double homeobox 4
External IDs	OMIM: 606009 GeneCards: DUX4
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q35.2 Start 190,173,774 bp[1] End 190,185,942 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte sural nerve smooth muscle tissue duodenum cervix fundus urinary bladder left uterine tube pituitary gland canal of the cervix n/a More reference expression data BioGPS n/a
Gene ontology Molecular function DNA binding transcription cis-regulatory region binding protein binding RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA-binding transcription activator activity, RNA polymerase II-specific sequence-specific double-stranded DNA binding Cellular component nuclear membrane nucleus nucleoplasm nucleolus cytosol Golgi apparatus Biological process negative regulation of G0 to G1 transition regulation of transcription, DNA-templated transcription, DNA-templated negative regulation of cell population proliferation positive regulation of transcription by RNA polymerase II apoptotic process transcription by RNA polymerase II multicellular organism development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 100288687 n/a Ensembl ENSG00000260596 ENSG00000283949 n/a UniProt Q9UBX2 n/a RefSeq (mRNA) NM_001205218 NM_001278056 NM_001293798 NM_001306068 NM_001363820 n/a RefSeq (protein) NP_001280727 NP_001292997 NP_001350749 n/a Location (UCSC) Chr 4: 190.17 – 190.19 Mb n/a PubMed search [2] n/a
Wikidata
View/Edit Human

Double homeobox, 4 also known as DUX4 is a protein which in humans is encoded by the DUX4 gene.^[3] Its misexpression is the cause of facioscapulohumeral muscular dystrophy (FSHD).

Gene

This gene is located within a D4Z4 macrosatellite repeat array in the subtelomeric region of chromosome 4q35. The D4Z4 repeat array contains 11-150 D4Z4 repeats in the general population; a highly homologous D4Z4 repeat array has been identified on chromosome 10. The gene consists of three exons. Exons 1 and 2 are present in each D4Z4 repeat. Only one copy of exon 3 is present, telomeric to the D4Z4 repeat array.^[4] The open reading frame (ORF) is entirely contained within exon 1 and contains two homeoboxes.^[4] Exons 2 and 3 encode for the three prime untranslated region (3′-UTR).^[4] In certain haplotypes, exon 3 contains a polyadenylation signal.^[4] There was no evidence for transcription from standard cDNA libraries however RT-PCR and in-vitro expression experiments indicate that the ORF is transcribed.^[5]

The repeat-array and ORF are conserved in other mammals.

Structure

DUX4 protein is 424 amino acids long.^[4] Two homeodomains are situated at the N-terminus. A transcription-activating domain (TAD) and p300-binding domain are situated at the C-terminus. The TAD encompasses a potential nine amino acid TAD (9aaTAD).^[4]

The two homeodomains and TAD have well-defined tertiary structure.^[4] The region between the second homeodomain and TAD is predicted to be disordered.^[4]

DUX4 transcripts can be spliced to produce either DUX4-S (short) or DUX4-FL (full length) mRNAs. DUX4-FL mRNA encodes for the entire DUX4 protein. DUX4-S mRNA encodes for a partial DUX4 protein, which lacks the transcription-activating domain.^[4]

Function

DUX4 protein a transcriptional activator of many genes, one example being paired-like homeodomain transcription factor 1 (PITX1).^[5] It likely stimulates zygotic genome activation.^{[citation needed]}

The two homeodomains allow DUX4 protein to bind to DNA.^[4] The C-terminal domain is involved in target gene activation.^[4]

DUX is normally expressed in the testes, thymus, and cleavage-stage embryos.^[6]

Clinical significance

Inappropriate expression of DUX4 in muscle cells is the cause of facioscapulohumeral muscular dystrophy (FSHD).^[7][8]

Overexpression of DUX4 due to translocations can cause B-cell leukemia.^[6] A translocation that merges DUX4 with CIC can cause an aggressive type of sarcoma.^[9]