Double homeobox protein 4

Function

Transcription factor that is selectively and transiently expressed in cleavage-stage embryos. Binds to double-stranded DNA elements with the consensus sequence 5'-TAATCTAATCA-3'. 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. Involved in transcriptional regulation of numerous genes, primarily as transcriptional activator, but also mediates repression of a set of target genes. Promotes expression of ZSCAN4 and KDM4E, two proteins with essential roles during early embryogenesis. Promotes nuclear translocation of CTNNB1/beta-catenin and its subsequent activation of target genes. Heterologous expression in cultured embryonic stem cells mediates transcription of HERVL retrotransposons and transcripts derived from ACRO1 and HSATII satellite repeats. May activate expression of PITX1. May regulate microRNA (miRNA) expression. Inappropriate expression can inhibit myogenesis and promote apoptosis.

Classification

Family (Pfam)

PF00046 Homeodomain

InterPro

HD, Homeobox_regulator, Homeodomain-like_sf, HTH_motif

Functional cluster

Eukaryotic Transcription Factors & related

Experimental structures · PDB · 11

• 5Z2S X-ray 1.50A
• 5Z2T X-ray 2.62A
• 5Z6Z X-ray 2.30A
• 5ZFW X-ray 2.10A
• 5ZFY X-ray 2.30A
• 5ZFZ X-ray 1.90A
• 6A8R X-ray 1.60A
• 6DFY X-ray 2.62A
• 6E8C X-ray 2.12A
• 6U81 X-ray 2.34A
• 6U82 X-ray 3.21A

A predicted model is available from AlphaFold.

Gene Ontology · 17

• GO:0005737 cytoplasm
• GO:0031965 nuclear membrane
• GO:0005730 nucleolus
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific
• GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific
• GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
• GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding
• GO:1990837 sequence-specific double-stranded DNA binding
• GO:0000976 transcription cis-regulatory region binding
• GO:0006915 apoptotic process
• GO:0006351 DNA-templated transcription
• GO:0008285 negative regulation of cell population proliferation
• GO:0070317 negative regulation of G0 to G1 transition
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0006357 regulation of transcription by RNA polymerase II

Disease associations

• facioscapulohumeral muscular dystrophy 1 MONDO:0008030

Neighborhood · nearest proteins

Related proteins · sequence + function similarity

• Double homeobox protein 4-like protein 7 1.00
• Double homeobox protein 4-like protein 5 1.00
• Double homeobox protein 4-like protein 3 1.00
• Double homeobox protein 4-like protein 2 1.00
• Double homeobox protein 4-like protein 4 1.00
• Double homeobox protein 4C 0.98
• Tetrapeptide repeat homeobox protein 2 0.83
• Homeobox protein Hox-B2 0.81
• Homeobox protein Hox-B2 0.81
• Homeobox protein MIXL1 0.81
• Mesoderm posterior protein 2 0.81
• Homeobox protein VENTX 0.80

Co-cited proteins · studied together in the literature

• Double homeobox protein 4C 3 shared papers
• Double homeobox protein 1 1 shared papers
• CREB-binding protein 1 shared papers
• Histone acetyltransferase p300 1 shared papers

Literature · 20 cited papers

• Antagonism Between DUX4 and DUX4c Highlights a Pathomechanism Operating Through beta-Catenin in Facioscapulohumeral Muscular Dystrophy. Front. Cell Dev. Biol. · 2022
• Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA. Cell Rep. · 2018
• Structural basis for multiple gene regulation by human DUX4. Biochem. Biophys. Res. Commun. · 2018
• DUX4HD2-DNAERG structure reveals new insight into DUX4-Responsive-Element. Leukemia · 2019
• Comment on structural basis of DUX4/IGH-driven transactivation. Leukemia · 2018
• Functional domains of the FSHD-associated DUX4 protein. Biol. Open · 2018
• Structural basis of DUX4/IGH-driven transactivation. Leukemia · 2018
• The DUX4 homeodomains mediate inhibition of myogenesis and are functionally exchangeable with the Pax7 homeodomain. J. Cell Sci. · 2017
• Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat. Genet. · 2017
• Conservation and innovation in the DUX4-family gene network. Nat. Genet. · 2017
• Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. Mol. Ther. · 2016
• DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes. Nucleic Acids Res. · 2016
• … and 8 more in the literature graph