DUX4

[[File:A schematic of D4Z4 locus on chromosome 4.jpg|thumb|right|alt=D4Z4 array diagram|400px|D4Z4 array with three D4Z4 repeats and the 4qA allele

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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. The open reading frame (ORF) is entirely contained within exon 1 and contains two homeoboxes. Exons 2 and 3 encode for the three prime untranslated region (3′-UTR). In certain haplotypes, exon 3 contains a polyadenylation signal. There was no evidence for transcription from the standard cDNA libraries however RT-PCR and in-vitro expression experiments indicate that the ORF is transcribed.{{cite web | title = Entrez Gene: DUX4 Double homeobox, 4 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=22947 | access-date = }}

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

DUX4 protein is 424 amino acids long. 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).

The two homeodomains and TAD have well-defined tertiary structures. The region between the second homeodomain and TAD is predicted to be disordered.{{cite journal |last1=Schätzl |first1=T |last2=Kaiser |first2=L |last3=Deigner |first3=HP |title=Facioscapulohumeral muscular dystrophy: genetics, gene activation, and downstream signalling with regard to recent therapeutic approaches: an update. |journal=Orphanet Journal of Rare Diseases |date=12 March 2021 |volume=16 |issue=1 |pages=129 |doi=10.1186/s13023-021-01760-1 |pmid=33712050|pmc=7953708 |doi-access=free }}

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.

The DUX4 protein is a transcriptional activator of many genes, one example being paired-like homeodomain transcription factor 1 (PITX1). It likely stimulates zygotic genome activation.{{Citation needed|date=May 2021}}

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

DUX is normally expressed in the testes, thymus, and cleavage-stage embryos.{{cite journal | vauthors = Lee JK, Bosnakovski D, Toso EA, Dinh T, Banerjee S, Bohl TE, Shi K, Orellana K, Kyba M, Aihara H | display-authors = 6 | title = Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA | journal = Cell Reports | volume = 25 | issue = 11 | pages = 2955–2962.e3 | date = December 2018 | pmid = 30540931 | doi = 10.1016/j.celrep.2018.11.060 | doi-access = free | pmc = 6463520 }}

Inappropriate expression of DUX4 in muscle cells is the cause of facioscapulohumeral muscular dystrophy (FSHD).{{cite journal | vauthors = Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, Snider L, Straasheijm KR, van Ommen GJ, Padberg GW, Miller DG, Tapscott SJ, Tawil R, Frants RR, van der Maarel SM | display-authors = 6 | title = A unifying genetic model for facioscapulohumeral muscular dystrophy | journal = Science | volume = 329 | issue = 5999 | pages = 1650–3 | date = September 2010 | pmid = 20724583 | pmc = 4677822 | doi = 10.1126/science.1189044 | bibcode = 2010Sci...329.1650L }}{{cite journal | vauthors = Jones TI, Chen JC, Rahimov F, Homma S, Arashiro P, Beermann ML, King OD, Miller JB, Kunkel LM, Emerson CP, Wagner KR, Jones PL | display-authors = 6 | title = Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis | journal = Human Molecular Genetics | volume = 21 | issue = 20 | pages = 4419–30 | date = October 2012 | pmid = 22798623 | pmc = 3459465 | doi = 10.1093/hmg/dds284 }}

Overexpression of DUX4 due to translocations can cause B-cell leukemia. A translocation that merges DUX4 with CIC can cause an aggressive type of sarcoma.{{cite journal | vauthors = Wong D, Yip S | title = Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor | journal = The Journal of Pathology | volume = 250 | issue = 5 | pages = 532–540 | date = April 2020 | pmid = 32073140 | doi = 10.1002/path.5400 | url = | doi-access = free }}

• Homeobox
• PITX1

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Category:Genes

Category:Human proteins

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