DUX4

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).

DUX4
Identifiers
Aliases	DUX4, DUX4L, double homeobox 4
External IDs	OMIM: 606009; GeneCards: DUX4; OMA:DUX4 - orthologs
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 gonad monocyte sural nerve left testis muscle of thigh right testis primary visual cortex smooth muscle tissue duodenum apex of heart 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

Gene

D4Z4 array with three D4Z4 repeats and the 4qA allele

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
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.^[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]

See also

• Homeobox
• PITX1

References

1. ENSG00000283949 GRCh38: Ensembl release 89: ENSG00000260596, ENSG00000283949 – Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. Gabriëls J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM, et al. (August 1999). "Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element". Gene. 236 (1): 25–32. doi:10.1016/S0378-1119(99)00267-X. PMID 10433963.
4. Schätzl, T; Kaiser, L; Deigner, HP (12 March 2021). "Facioscapulohumeral muscular dystrophy: genetics, gene activation and downstream signalling with regard to recent therapeutic approaches: an update". Orphanet Journal of Rare Diseases. 16 (1): 129. doi:10.1186/s13023-021-01760-1. PMC 7953708. PMID 33712050.
5. "Entrez Gene: DUX4 Double homeobox, 4".
6. Lee JK, Bosnakovski D, Toso EA, Dinh T, Banerjee S, Bohl TE, et al. (December 2018). "Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA". Cell Reports. 25 (11): 2955–2962.e3. doi:10.1016/j.celrep.2018.11.060. PMC 6463520. PMID 30540931.
7. Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, et al. (September 2010). "A unifying genetic model for facioscapulohumeral muscular dystrophy". Science. 329 (5999): 1650–3. Bibcode:2010Sci...329.1650L. doi:10.1126/science.1189044. PMC 4677822. PMID 20724583.
8. Jones TI, Chen JC, Rahimov F, Homma S, Arashiro P, Beermann ML, et al. (October 2012). "Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis". Human Molecular Genetics. 21 (20): 4419–30. doi:10.1093/hmg/dds284. PMC 3459465. PMID 22798623.
9. Wong D, Yip S (April 2020). "Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor". The Journal of Pathology. 250 (5): 532–540. doi:10.1002/path.5400. PMID 32073140.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.