DUX4 — Mediated Wiki

'''Double homeobox, 4''' also known as '''DUX4''' is a protein which in humans is encoded by the ''DUX4'' gene.<ref name="pmid10433963">{{cite journal | vauthors = Gabriëls J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM, Padberg GW, Frants RR, Hewitt JE, Collen D, Belayew A | display-authors = 6 | title = Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element | journal = Gene | volume = 236 | issue = 1 | pages = 25–32 | date = August 1999 | pmid = 10433963 | doi = 10.1016/S0378-1119(99)00267-X }}</ref> Its misexpression is the cause of facioscapulohumeral muscular dystrophy (FSHD).

==Gene== [[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 {| style="width: 100%; |- | '''CEN''' || centromeric end || '''TEL''' || telomeric end |- | '''NDE box''' || non-deleted element || '''PAS''' || polyadenylation site |- | '''triangle''' || D4Z4 repeat|| '''trapezoid''' || partial D4Z4 repeat |- | '''white box''' || pLAM || '''gray boxes''' || DUX4 exons 1, 2, 3 |- | colspan="4" style="text-align: center; background: #cccdcf;" | '''arrows''' |- | '''corner''' || promoters || '''straight''' || RNA transcripts |- | '''black''' || sense || '''red''' || antisense |- | '''blue''' || DBE-T || '''dashes''' || dicing sites |} ]] 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.<ref name="Schatzl2021FSHD_Update" /> The open reading frame (ORF) is entirely contained within exon 1 and contains two homeoboxes.<ref name="Schatzl2021FSHD_Update" /> Exons 2 and 3 encode for the three prime untranslated region (3′-UTR).<ref name="Schatzl2021FSHD_Update" /> In certain haplotypes, exon 3 contains a polyadenylation signal.<ref name="Schatzl2021FSHD_Update" /> 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.<ref name="entrez">{{cite web | title = Entrez Gene: DUX4 Double homeobox, 4 | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=22947 | access-date = }}</ref>

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

==Structure== DUX4 protein is 424 amino acids long.<ref name="Schatzl2021FSHD_Update" /> 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).<ref name="Schatzl2021FSHD_Update" />

The two homeodomains and TAD have well-defined tertiary structures.<ref name="Schatzl2021FSHD_Update" /> The region between the second homeodomain and TAD is predicted to be disordered.<ref name="Schatzl2021FSHD_Update">{{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 }}</ref>

''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.<ref name="Schatzl2021FSHD_Update" />

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

The two homeodomains allow DUX4 protein to bind to DNA.<ref name="Schatzl2021FSHD_Update" /> The C-terminal domain is involved in target gene activation.<ref name="Schatzl2021FSHD_Update" />

DUX is normally expressed in the testes, thymus, and cleavage-stage embryos.<ref name="Kyba 2018">{{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 }}</ref>

==Clinical significance==

Inappropriate expression of DUX4 in muscle cells is the cause of facioscapulohumeral muscular dystrophy (FSHD).<ref name="pmid20724583">{{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 }}</ref><ref name="pmid22798623">{{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 }}</ref>

Overexpression of DUX4 due to translocations can cause B-cell leukemia.<ref name="Kyba 2018" /> A translocation that merges DUX4 with CIC can cause an aggressive type of sarcoma.<ref name="pmid32073140">{{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 }}</ref>

In common biomedical model organisms, rhesus macaques and crab-eating macaques, the D4Z4 array syntenic to the human Chr4 array is different from its human counterpart.<ref>{{Cite journal |last=Fu |first=Lianting |last2=Chen |first2=Jieyi |last3=Lian |first3=Da |last4=Du |first4=Siyuan |last5=Wu |first5=Dongya |last6=Yang |first6=Chentao |last7=Wang |first7=Ziyi |last8=Ma |first8=Hongyi |last9=Li |first9=Zhengtong |last10=Lake |first10=Nicole J. |last11=Yang |first11=Xiangyu |last12=Shi |first12=Yongyong |last13=Zhang |first13=Guojie |last14=Ma |first14=Kaiyue |last15=Mao |first15=Yafei |date=2026-05-15 |title=A long-read human pangenome initiative for comprehensive interpretation of nuclear-embedded mitochondrial DNA |url=https://www.nature.com/articles/s41467-026-71348-5 |journal=Nature Communications |language=en |volume=17 |issue=1 |pages=4371 |doi=10.1038/s41467-026-71348-5 |issn=2041-1723}}</ref> In macaques, all copies are towards the centromeric end, with the most centromeric copy potentially being the one that expresses. In macaques, in between ''DUX4'' copies, there is a NUMT sequence. The NUMT sequence changed the methylation landscape, making this hypermethylated region fragmental.

== See also == * Homeobox * PITX1

== References == {{reflist}}

Category:Genes Category:Human proteins