This article has been corrected. See Ulster Med J. This article has been cited by other articles in PMC. Abstract HOX genes are evolutionarily highly conserved.
Open in a separate window. Fig 1. Fig 2. Fig 3. Lewis EB. A gene complex controlling segmentation in Drosophila. Origins of anteroposterior patterning and Hox gene regulation during chordate evolution. Duboule D. Lewin B. Genes VII. Oxford: Oxford University Press; Homeodomains bind related targets in DNA; pp. Kmita M, Duboule D. Organizing axes in time and space; 25 years of colinear tinkering.
Temporal colinearity and the phylotypic progression: a basis for the stability of a vertebrate Bauplan and the evolution of morphologies through heterochrony.
A large Turkish kindred with syndactyly type II synpolydactyly. Field investigation, clinical and pedigree data. J Med Genet. Localization of the syndactyly type II synpolydactyly locus to 2q31 region and identification of tight linkage to HOXD8 intragenic marker. Hum Mol Genet. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD Am J Hum Genet.
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A novel stable polyalanine [poly A ] expansion in the HOXA13 gene associated with hand-foot-genital syndrome: proper function of poly A -harbouring transcription factors depends on a critical repeat length? Hum Genet. Monodactylous limbs and abnormal genitalia are associated with hemizygosity for the human 2q31 region that includes the HOXD cluster. Mollard R, Dziadek M.
Homeobox genes from clusters A and B demonstrate characteristics of temporal colinearity and differential restrictions in spatial expression domains in the branching mouse lung.
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RNA Functions. Citation: Myers, P. Hox genes, a family of transcription factors, are major regulators of animal development. Unlike most genes, however, the order of Hox genes in the genome actually holds meaning. Aa Aa Aa. Hox Genes in Drosphila. Hox Genes in Mice and Other Vertebrates. On the left side of the panel, a diagram of the axial skeleton is shown, with specific vertebral elements shown in the right panel marked C, cervical; T, thoracic; L, lumbar, S, sacral. Wild-type, control elements from specific vertebral positions are denoted by letter and number.
The analogous segment from the paralogous mutants are shown on the right and left, with colored boxes for each paralogous mutant group. Developmental Dynamics , Hox5, Hox6, Hox9, Hox10, and Hox11 paralogous mutants. When paralogous deletions of Hox genes are made, these features do not develop normally, resulting in skeletal deformities. For example, when the paralogous Hox5 genes are deleted, a dorsal neural arch appears on C7 and T1 arrows similar to the normal C2 vertebrae, and ribs are initiated but not completed on T1.
When the paralogous Hox6 genes are deleted, no ribs form at T1. In contrast, when the Hox9 genes are deleted, additional ribs form at L1. Ribs are also formed from L1 to S1 when the Hox10 genes are deleted, and the fused sacral wings are absent at S1 in mice lacking Hox Paralogous Knockouts in Mice. Hox paralogous mutants.
Aqua-shaded areas demonstrate the regions of anterior homeotic transformations of the somite-derived primaxial phenotypes. Purple-shaded areas show the lateral plate-derived, abaxial phenotypes for each group.
The orange background highlights the regions of phenotypic overlap between adjacent paralogous mutants. When Hox6 is deleted, no ribs form at T1 and the ribs at T2 are incomplete. Deletion of Hox9 paralogs causes the inferior thoracic ribs to attach to the sternum, and ribs form on the L1 to L4 vertebrae.
In addition, two extra lumbar vertebrae are formed. Hox10 deletion causes formation of Tlike ribs on the lumbar vertebrae and partial ribs on the sacral vertebrae as well. Hox11 deletion prevents the formation of fused sacral wings, and the sacral vertebrae and the superior tail vertebrae develop into lumbar vertebrae.
Regardless of structural changes to individual vertebrae, the total number of vertebrae remains the same in all mice. One group of animal genes containing homeobox sequences is specifically referred to as Hox genes.
This cluster of genes is responsible for determining the general body plan, such as the number of body segments of an animal, the number and placement of appendages, and animal head-tail directionality. The first Hox genes to be sequenced were those from the fruit fly Drosophila melanogaster.
A single Hox mutation in the fruit fly can result in an extra pair of wings or even legs growing from the head in place of antennae this is because antennae and legs are embryologic homologous structures and their appearance as antennae or legs is dictated by their origination within specific body segments of the head and thorax during development.
Now, Hox genes are known from virtually all other animals as well. Figure 1. Shown here is the homology between Hox genes in mice and humans. Note how Hox gene expression, as indicated with orange, pink, blue, and green shading, occurs in the same body segments in both the mouse and the human.
While at least one copy of each Hox gene is present in humans and other vertebrates, some Hox genes are missing in some chromosomal sets. Alternatively, does the upregulated HOX bind to and activate a completely different set of genes whose function interferes with differentiation? Rather than competition and down-regulation of normal HOX target genes , this second mechanism would lead to inappropriate upregulation of other genes. Such issues are also clouded by the fact that ectopic expression of certain Xenopus Hox proteins have been shown to lead to increased expression of other Hox genes transcribed from the same or different cluster [ 39 ].
The term homeobox is used to describe this gene family because aberrant expression of these genes can, in certain situations, result in homeosis, i. However, it should also be noted that the subgroup of homeobox genes encoded at the 4 HOX loci are derived from two rounds of genomic duplication and thus the 39 HOX genes share highly similar protein sequences Figure 2 and Figure S1. Perhaps the paralogs from the four HOX loci e. Unfortunately, to date, very few studies have compared the function of different HOX genes in mouse or human cells.
We note that the International Mouse Phenotype Consortium [ 41 ] is creating mice having knockout alleles for Hox proteins.
As described above, there is evidence that some mouse HOX paralogs can substitute for each other in kidney development. However, functional equivalence is not always the rule. Because the DNA binding homeodomain is highly similar amongst the HOX proteins especially when comparing paralogs , it has been proposed that protein-protein interactions mediated by amino acids outside of the DNA binding domain may confer functional specificity. Aligning the sequences adjacent to the hexapeptide has identified amino acids that are conserved within paralog groups and it has been suggested that these paralog-specific amino acids may fine tune HOX-PBX interactions and provide DNA binding specificity [ 48 ].
Similar, but distinct, partners may confer additional specificity of binding via a functional cooperation with various HOX proteins reviewed in [ 6 ]. Further investigation of functional specificity of the 39 HOX genes requires a thorough analysis of their protein interaction partners. A major problem with identifying interaction partners of the HOX proteins is that the HOX proteins are generally expressed at fairly low levels, even in cancer cells.
Because of the low expression levels, very large amounts of starting nuclear extract are required for mass spectrometry experiments. Another problem is that most commercial antibodies to the HOX proteins are of very low quality perhaps due to the strong evolutionary conservation of their protein sequences and cannot even detect exogenously expressed high levels of the target HOX protein.
Due to these two issues, it is likely that identification of interacting partners will require the use of overexpressed, tagged proteins. However, comparisons of different tags placed either at the N- or C-terminus, introduction of the tag into the endogenous locus, or carefully controlled expression of the tagged protein may partially alleviate these problems. Another issue could be that identification of bona fide HOX-interacting proteins may require that HOX proteins be bound to their genomic target sites.
This method identifies interaction partners of chromatin-bound proteins rather than using soluble nuclear extracts for the immunoprecipitation step. Because of their importance in normal development and their link to diseases such as aggressive prostate cancer, identifying regulatory elements bound by the HOX proteins should be of high priority to the scientific community. However, of the 39 human HOX proteins, only a few have been studied using genome-wide technologies. Binding sites for HOXC9 in neuroblastoma cells and HOXC6 in prostate cancer cells have been identified using an antibody to a tagged, exogenously expressed protein [ 49 , 56 ].
Modest success has been reported for the identification of binding sites for mouse HOX proteins. The distal binding sites have a high overlap with the active enhancer mark H3K27Ac.
As is consistent with the activity of a transcription factor that binds to enhancers, it has been suggested that HOX proteins could possibly regulate multiple steps of transcription reviewed in [ 61 ].
For example, the HOX proteins could function as pioneer transcription factors that can assist in switching histone marks from inactive to active by recruiting chromatin remodelers, such as Trithorax group and Polycomb group proteins, to distal regulatory elements.
Clearly, a genomic binding profile analysis of all 39 human HOX proteins in a variety of different normal and diseases tissues such as cancer would be highly instructive. Motifs identified using in vitro and in vivo methods [ 62 , 63 , 64 ] indicate that HOX binding sites are short AT-rich sequences e.
Sequences similar to this motif are found throughout the genome and it is likely that additional information is required to specify in vivo binding of a HOX family member. As discussed above, cooperative binding with other proteins may help to direct a HOX protein to a subset of the AT-rich HOX motifs found throughout the genome.
If so, then a search for HOX interaction partners is critical. In addition to the mass spectrometry methods described above, another method by which cooperative binding partners can be identified is to perform motif analysis of in vivo binding sites and look for motifs for other transcription factors. Similar studies may reveal tissue-specific interaction partners for HOX proteins.
Many HOX-bound enhancers have multiple low affinity binding sites that are called homotypic binding clusters. It has been suggested that specificity of HOX protein recruitment could be achieved by using a cluster of low affinity HOX binding sites even if HOX binding to individual motifs is less precise [ 66 ]. Support for this mechanism could be obtained from a motif analysis of the genomic neighborhood of a set of in vivo HOX binding sites; clusters of AT-rich motifs in the neighborhood of the peak centers may be present at the robust peaks.
However, if so, this could be alleviated by transiently expressing higher levels of tagged factors. We suggest that the creation of a library of tagged, inducible constructs for all 39 HOX proteins would be a useful addition to the field. If so, then technological modifications to the standard ChIP assay may be needed. For example, Sheth et al. Lacin et al. Newer genome-wide immunoprecipitation-based methods, such as DAM-IP [ 69 ], may be useful for identifying genomic binding sites of the human HOX proteins.
However, this would limit the binding site identification to that cell line. Similar to the tagged expression constructs described above, a library of inducible HOX proteins fused to an enzyme that can mark the environment of a HOX genomic binding site would be useful for the field. As noted above, numerous HOX proteins have been shown to be upregulated in tumors and can serve as robust biomarkers for clinical diagnosis and treatment [ 21 , 22 , 23 , 33 , 35 ].
Importantly, evidence also suggests that certain HOX genes are drivers of tumorigenesis. For example, several studies have shown that reduction of levels of an overexpressed HOX can move cancer cells towards a more normal phenotype.
These studies demonstrate that, at least in some cases, HOX genes can be drivers of tumorigenesis and are not simply upregulated as a consequence of neoplastic transformation. Such studies suggest that inhibition of HOX levels or activity may be a rationale therapeutic option. Although it may seem logical to attempt to develop direct inhibitors of HOX proteins that could reduce their activity in cancer cells, transcription factors are thought to be quite difficult to target in this way.
Encouragingly, Morgan and colleagues have developed a cell permeable amino acid peptide called HXR9 that can disrupt and thus functionally inactivate interaction of a subset of HOX proteins members of paralogue groups with a common cofactor PBX.
They show that HXR9 can block the growth of prostate tumors in a mouse xenograph model system [ 32 ]. HXR9 has also been shown to inhibit the growth of a range of other tumor types in mouse xenograft models see Table 1 in [ 71 ]. To date, large-scale screening experiments for small molecule inhibitors of human HOX proteins have not yet been reported.
The investigators further showed that CSRM can inhibit cell growth and induce apoptosis in vitro in several prostate cancer cell lines that express moderate to high levels of ONECUT2 and that the compound can suppress prostate cancer growth and metastasis in a nude mouse model system. Thus, it would perhaps be useful to screen chemical libraries for inhibitors of the HOX proteins. Methods other than directly inhibiting the function of a HOX protein could also be explored.
Although some of these methods have entered into clinical treatment for other genes, they are not considered as robust as using a small molecule inhibitor. Another approach could be to inhibit the activity of an enzyme that is required for HOX expression. Inhibition of MYC function has been achieved by targeting a component of a co-activator complex that regulates the MYC oncogene.
MYC expression has been shown to be driven by BET bromodomain proteins, which bind to acetylated histone tails and facilitate transcriptional activation. We do not yet know all of the regulatory elements and proteins that control HOX gene expression; 3-dimensional chromatin interaction data and epigenomic mapping in cancer cells may provide useful information. Finally, the identification of gene networks that are activated by an aberrantly expressed HOX protein may identify more easily druggable enzymes whose activity is responsible for the HOX-mediated disease phenotype.
For example, Morsi El-Kadi et al. This suggests that increased expression of Hoxb4 may lead to upregulation of Ras; in this example, targeting the Ras pathway may be one approach to inhibit Hoxb4.
The member human HOX family is important for normal development and has been implicated in the initiation and progression of human diseases. However, this family is severely under-studied, likely due to idiosyncratic details of their structure, expression, and function.
We suggest that a concerted and collaborative effort to produce genome-wide binding profiles, identify interacting partners, and develop HOX network inhibitors would lead to a deeper understanding of human development and disease Box 1. Do HOX proteins have post-DNA binding specificity or is ostensible specificity achieved mainly via temporal and spatial expression patterns?
Comprehensive genome-wide mapping of the 39 human HOX proteins in multiple tissues and disease states. Comprehensive identification of protein partners of HOX family members in the nucleoplasm and when bound to chromatin. Do HOX proteins represent a relatively untapped cohort of potential therapeutic targets? Agents that inhibit the function of specific HOX family members or the activity of components of specific HOX-mediated networks. Expanded analysis of HOX proteins as disease-specific biomarkers and initiation of clinical trials of existing and future HOX-related inhibitors.
Conceptualization, Z.
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