Disease relevance of HOXD4

• The multiple transcripts of the human HOX-5.1 gene are expressed differentially in tissue- and stage-specific patterns during embryogenesis, and differentially induced by retinoic acid (RA) in human embryonal carcinoma (EC) NT2/D1 cells [1].
• The p.Glu81Val mutation of HOXD4 thus results in a partial loss-of-function, which might be involved in childhood ALL [2].
• These comprised the germline c.242A>T (p.Glu81Val) missense mutation of HOXD4, detected in two children diagnosed with acute lymphoblastic leukemia (ALL) [2].

High impact information on HOXD4

• A fusion gene consisting of a heat shock promoter attached to the human Hox-4.2 gene was introduced into the Drosophila genome, and its regulatory and developmental effects were assayed after heat shock [3].
• The HOX3D protein, and those encoded by the downstream gene HOX3E and its paralog HOX4B are instead inactive [4].
• The comparison to Hoxd-4 and Isl-1 indicates that this role in chondrogenesis is specific to proteins of the Hox class [5].
• (i) Most of PBX N terminal to the homeodomain is required for efficient cooperative binding with HOXD4 and HOXD9 [6].
• (iii) Although MEIS does not cooperatively bind DNA with ANTP class HOX proteins, it does form a trimer as a non-DNA-binding partner with DNA-bound PBX-HOXD4 [6].

Chemical compound and disease context of HOXD4

• We have identified a 185-bp retinoid-responsive transcriptional enhancer 5' of the human HOXD4 gene, which regulates inducibility of the gene in embryonal carcinoma cells through a pattern of DNA-protein interaction on at least two distinct elements [7].

Biological context of HOXD4

• In this study, we have used transgenic analysis of the human HOXD4 locus to identify one neural and two mesodermal 3' enhancers that are capable of mediating the proper anterior limits of expression in the hindbrain and paraxial mesoderm (somites), respectively [8].
• The HOXD4 enhancer directs expression of a lacZ reporter gene in the neural tube of transgenic mouse embryos in a time-regulated and regionally restricted fashion, reproducing part of the anterior neuroectodermal expression pattern of the endogenous Hoxd-4 gene [7].
• Administration of retinoic acid to developing embryos causes alterations in the spatial restriction of the transgene expression domain, indicating that the HOXD4 enhancer is also a retinoid-responsive element in vivo [7].
• Induction of the HOXD4 promoter-enhancer in the presence of a selective RAR alpha antagonist indicated that the RAR alpha-dependent RAR beta activation is nevertheless a necessary step in HOX gene activation [9].
• We have studied the regulation of the early activated HOXD4 gene, which is expressed in human embryogenesis in multiple transcripts generated by the developmentally controlled use of alternative transcription start sites and polyadenylation signals [9].

Anatomical context of HOXD4

• We have analyzed the expression of homeoproteins of the HOX family in resting and activated lymphoid cells and in neoplastic lymphoid cell lines by the use of monoclonal antibodies (MoAbs) already shown to react with the homeoproteins HOXA10, HOXC6, and HOXD4, respectively [10].
• Purified nucleoli from stimulated T lymphocytes, and Raji cells contain an activity capable of binding, in a gel retardation assay, to an oligonucleotide specifically recognised by the HOXD4 homeoprotein [11].
• Low levels of HOXD4 and HOXD9 induction were observed in two and one RA-treated NB cell line, respectively [12].
• In addition to directing expression in the central nervous system (CNS) up to the correct rhombomere 6/7 boundary in the hindbrain, the neural enhancer also mediates a three rhombomere anterior shift from this boundary in response to retinoic acid (RA), mimicking the endogenous Hoxd4 response [8].
• Grafting of somites or retinoic acid-loaded beads beneath the rostral hindbrain induced the formation of somatic motoneurones in rhombomere 4 only, and Hox genes normally expressed more caudally (Hoxa3, Hoxd4) were induced in this region [13].

Associations of HOXD4 with chemical compounds

• In vitro and transgenic analysis of a human HOXD4 retinoid-responsive enhancer [7].
• Synthesis of NH2-VYPWMK hexapeptide confirmed this prediction; and an alanine scan of HOXD4 ablated binding by mAb 10D11 when amino acids in the putative epitope were mutated [14].
• Using antibodies to XlHbox 1 (similar to Hox 3.3 or C6) and Hox 4.2 (or D4), we showed that there is a homeoprotein gradient within the feather buds, and that the expression pattern is position-specific [15].

Physical interactions of HOXD4

• Conversely, the Polycomb group (PcG) protein Ying-Yang 1 (YY1) binds to an internucleosomal linker and represses Hoxd4 transcription before and during transcriptional activation [16].

Regulatory relationships of HOXD4

• An autoregulatory element was shown to recruit HOXD4 and its cofactor PBX1 and to positively regulate Hoxd4 expression in differentiating P19 cells [16].

Other interactions of HOXD4

• Importantly, N-terminal arm residues 2 and 3, which distinguish the binding of HOXA1 and HOXD4 monomers, play no role in the specificity of their complexes with PBX [17].
• The HOX4A gene, one of the homeobox-containing genes on human chromosome 2, has been isolated by screening a genomic cosmid library with a HOX4B cDNA probe [18].

Analytical, diagnostic and therapeutic context of HOXD4

• This activity is specifically removed by anti-HOXD4 antibodies and is found associated in southwestern blots with a single band with an apparent M(r) of 30,000, corresponding to that of recombinant HOXD4 [11].

References