Double homeobox protein 4

Definition:

[Isoform 1]: 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 mediates also repression of a set of target genes. Promotes expression of ZSCAN4 and KDM4E, two proteins with essential roles during early embryogenesis. Heterologous expression in cultured embryonic stem cells mediates also 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.; [Isoform 2]: Probably inactive as a transcriptional activator, due to the absence of the C-terminal region that is important for transcriptional activation. Can inhibit transcriptional activation mediated by isoform 1. Heterologous expression of isoform 2 has no deleterious effect on cell survival.

References:

[1]. Xue Dong, et al. Structural basis of DUX4/IGH-driven transactivation. Leukemia. 2018 Jun;32(6):1466-1476. [Content Brief]

[2]. Hiroaki Mitsuhashi, et al. Functional domains of the FSHD-associated DUX4 protein. Biol Open. 2018 Apr 26;7(4):bio033977. [Content Brief]

[3]. Jennifer L Whiddon, et al. Conservation and innovation in the DUX4-family gene network. Nat Genet. 2017 Jun;49(6):935-940. [Content Brief]

[4]. Xue Dong, et al. DUX4HD2-DNAERG structure reveals new insight into DUX4-Responsive-Element. Leukemia. 2019 Feb;33(2):550-553. [Content Brief]

[5]. John K Lee, et al. Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA. Cell Rep. 2018 Dec 11;25(11):2955-2962.e3. [Content Brief]

[6]. Jennifer Cj Chen, et al. Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. Mol Ther. 2016 Aug;24(8):1405-11. [Content Brief]

[7]. Si Ho Choi, et al. DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes. Nucleic Acids Res. 2016 Jun 20;44(11):5161-73. [Content Brief]

[8]. Petr Dmitriev, et al. Defective regulation of microRNA target genes in myoblasts from facioscapulohumeral dystrophy patients. J Biol Chem. 2013 Dec 6;288(49):34989-5002. [Content Brief]

[9]. Peter G Hendrickson, et al. Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat Genet. 2017 Jun;49(6):925-934. [Content Brief]

[10]. Darko Bosnakovski, et al. The DUX4 homeodomains mediate inhibition of myogenesis and are functionally exchangeable with the Pax7 homeodomain. J Cell Sci. 2017 Nov 1;130(21):3685-3697. [Content Brief]

[11]. Manjusha Dixit, et al. DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18157-62. [Content Brief]

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