What do homeotic genes direct

The dual copies are expressed in varying degrees from antero-central to telson. Notedly, the telson is formed posterior to terminalia anus. It would be interesting to delete one or multiple copies of each of these Hox genes and observe the changes in body patterning.

The tagmatization could be affected to the extent that the body form might become less elongated, as is the case with Opiliones, harvestmen, or instigated to form a telson-less scorpion Sharma et al. The opposite spectrum of body formation is seen in Tardigrades, in which deletion of several Hox genes correlates with their compact body plan with simpler, repetitive, and less four number of segments Smith et al.

Other than the levels of HOX, structural modifications in the transcription factors can help in diverse functions. Recent experiments with flies provided evidence of functional conservation of mouse Hox genes. Singh et al. The ortholog-specific interaction leads to differential occupancy of HoxA1 across the genome. This study strongly supports the notion of evolutionary modularity in Hox complex by causing structural changes in HOX that lead to similar yet functionally divergent protein products Singh et al.

An ordered arrangement of Hox could have played an important role in their sequential co-regulation along the AP axis, as indicated by our understanding of BX-C regulation. One can consider Hox genes as switches to control different electrical equipment at home. They can be present anywhere across the house and can still function, as is the case of an octopus. But clustering on a switchboard gives quick, precise, and perhaps, robust control over the spatio-temporal regulation of Hox genes. This modularity could have been one reason for arthropods to surpass mollusks as the richest bio-diverse species on our planet Benton, Many genes are co-regulated in different organisms Snel et al.

Overall, clustering is more abundant in vertebrates than invertebrates Elizondo et al. Nevertheless, in addition to clustering, the ordering is an important property of Hox complexes that need to be pondered upon. Understanding them in the context of gene clusters, including Hox complexes, will be riveting. The Hox genes have a tremendous potential to modulate diversity by teaming up with multiple partners and setting a stage for downstream players in various axes.

Different combinations of cis- and trans- regulators together bring about manifold changes that can drive evolution.

Classically, mutations in Hox genes are associated with the homeotic transformation of one body segment into another, a process called homeosis Lewis, These mutations transformed embryonic segments, and therefore the Hox genes were established as the regulators during embryonic development Pradel and White, Recent studies opened new horizons to understand the role of Hox genes in an organism. A rising number of articles suggest their role beyond homeotic functions and embryonic development Wang et al.

The three genes of the bithorax complex, Ubx , abd-A , and Abd-B , have defined anterior limits of expression in Drosophila larvae. The larva undergoes metamorphosis during pupal stages of development, ultimately eclosing as adults.

One key event during this process is autophagy of most of the larval tissues, including the fat body, salivary glands, and trachea.

This is further coupled with the differentiation of adult tissues that goes on till eclosion. Down regulation of Ubx is accompanied by developmental and starvation-induced autophagy, whereas sustained expression of the Hox gene inhibits autophagy and delays metamorphosis Banreti et al.

Like the larval fat body, larval epithelial cells LECs also undergo apoptosis during metamorphosis. Further, another group of cells called histoblast nest cells HNCs differentiates to form adult abdominal epithelial cells during pupation. Moreover, HNC proliferation is hindered by abd-A down regulations, and the cells fail to form a complete epithelium in abd-A knocked down pupae. Similar reports for Abd-B were observed in testis development, where it remains active in pre-meiotic spermatocytes.

Tissue-specific knockdown of Abd-B in adult testes leads to a loss of maintenance of the stem cell niche required to produce normal sperms. This is because ABD-B has direct binding sites on src42A and sec63 , members of Boss signaling involved in testes formation and sperm differentiation. Abd-B also has an extended effect on the orientation of centrosomes and the division rates of germline stem cells Papagiannouli and Lohmann, Obtaining tissue-specific cells for further studies of Hox was a Herculean task a couple of years back, as one had to do neck-breaking dissections to get ounces of desirable material.

Although now, endogenous tagging of Hox genes has solved a lot of such problems. Cell sorting of fluorescently labeled HOX expressing tissues followed by multi -omics experiments can help us understand the genome-wide effects of HOX in adult tissues. Domsch et al. They utilized this resource to establish the role of Ubx as a major repressor of factors involved in alternate fate development in mesodermal cells.

In their recent work, Paul et al. The extraembryonic roles of Hox are more distinct in vertebrates. As early as , it was evident that Hox genes play a role in non-homeotic fashion owing to the near-complete loss of hair formation in mice deficient for HoxC Although the mouse also had patterning defects, hair growth was uniformly reduced across the body Awgulewitsch, Recent reports showed several HoxC genes in the dermal papilla and associated it with regional follicle variation.

In a mutant mouse line called Koala mutant, a 1 Mb inversion encompassed disintegration of HoxC4 to HoxC13 from the main complex leading to their misexpression. Similar deletion studies have identified the role of HoxA genes in mammary gland formation during specific transition developmental periods Lewis, Owing to their multifaceted roles during and after development, levels of Hox proteins need to be tightly regulated.

Misexpression of these genes has been observed in various cancers like breast cancer, melanoma, bone cancer, blood cancer, and colorectal cancer Shah and Sukumar, Central and posterior Hox genes, HoxA5 and HoxD9 , have been implicated in esophageal squamous cell carcinoma. Strikingly, they were found to localize more in the cytoplasm of the mucosa cells in esophageal cancer than in the nucleus in normal cellular conditions Takahashi et al.

Overexpression of posterior Hox genes, particularly HoxA, HoxB13, and HoxC10, is linked to the onset and tumor progression of ovarian, cervical, and prostate cancers Jung et al. Hox-associated cancer is not limited to genetic mutations.

Rauch et al. The study highlighted epigenetic misregulation as a putative cause for Hox-related lung tumors. Likewise, promoter methylation of HoxA5 and downregulation of HoxA10 are associated with progressive breast carcinoma. Misexpression studies in Drosophila confirmed the causal effect and established flies as a model to study Hox-associated oncogenesis. The outcome of the study was the ability of Dfd , Ubx , and abd-A genes to be leukemogenic when overexpressed in fat body and lamellocytes Ponrathnam et al.

Detailed understanding of Hox genes expression and interaction during embryogenesis, tissue formation, organogenesis, and cellular homeostasis is required to delineate their functional modalities. Due to their overarching involvement in multiple processes of body formation, patterning, and evolution, Hox genes occupy a prime position in our quest toward understanding these processes in depth.

A long-debated topic in the field of Hox genes was their presence in the form of clusters and the property of spatio-temporal collinearity. Some recent developments also demonstrated the functioning of Hox independent of clustering.

However, coordinated functioning is better when they are clustered together, as implied by the open for business model of the bithorax complex. Alterations of CRMs throughout the Hox led to a myriad of homeotic transformations. Similar genomic alterations across evolution might have experimented with Hox modules and their expression to bring about the enormous diversity we see today. Hox come together to set up the primary and secondary axes and provide constant inputs in different tissues, therefore orchestrating the developmental design sublimely.

In vivo experiments with the latest genome editing tools and a better understanding of non-coding DNA become important for comprehending the conductors of this symphony. RKM and NH conceived the design of the article and edited the manuscript.

Both authors contributed to the article and approved the submitted version. NH is a fellow of the Department of Biotechnology, Govt.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Soujanya, Sonu Yadav, and Lorraine Teron for carefully reviewing the manuscript. The authors would also like to extend gratitude toward Surbhi Lambhate for continuous discussions and suggestions while preparing the manuscript. Abzhanov, A. Crustacean malacostracan Hox genes and the evolution of the arthropod trunk. Development , — Akam, M.

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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. The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

National Center for Biotechnology Information , U. Journal List Cancers Basel v. Cancers Basel. Published online Mar 7. Zhifei Luo , Suhn K. Rhie , and Peggy J. Author information Article notes Copyright and License information Disclaimer. Received Feb 2; Accepted Mar 1. This article has been cited by other articles in PMC. Associated Data Supplementary Materials cancerss Abstract Homeobox genes HOX are a large family of transcription factors that direct the formation of many body structures during early embryonic development.

Introduction The homeobox gene family is the second largest family of transcription factors encoded in the human genome and consists of an estimated genes [ 1 ], each of which contains a nucleotide sequence that encodes a amino acid homeodomain that forms a helix-turn-helix structure.

Open in a separate window. Figure 1. Figure 2. Figure 3. Future Directions and Technological Challenges 3. Solving the HOX Specificity Paradox The term homeobox is used to describe this gene family because aberrant expression of these genes can, in certain situations, result in homeosis, i.

Technological Challenges 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. Identifying Target Genes of the Human HOX Proteins 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.

Technological Challenges 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. Technological challenges 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. Conclusions The member human HOX family is important for normal development and has been implicated in the initiation and progression of human diseases.

Box 1 The next phase of HOX exploration. Click here for additional data file. Author Contributions Conceptualization, Z. Conflicts of Interest The authors declare no conflict of interest. References 1. Vaquerizas J. A census of human transcription factors: function, expression and evolution. Lewis E. The Albert Lasker Medical Awards. Clusters of master control genes regulate the development of higher organisms. Garcia-Fernandez J. The genesis and evolution of homeobox gene clusters.

Merabet S. Trends Genet. Pearson J. Modulating Hox gene functions during animal body patterning. Rezsohazy R. Cellular and molecular insights into Hox protein action. Quinonez S. Human HOX gene disorders. Wellik D. Hox11 paralogous genes are essential for metanephric kidney induction. Genes Dev. Dereeper A. BMC Evol Biol. Nucleic Acids Res. Pfam Sanchez-Herrero E. Hox targets and cellular functions.

Scientifica Cairo ; Hombria J. Beyond homeosis--HOX function in morphogenesis and organogenesis. Sheth R. Cell Rep. Dhanasekaran S. Molecular profiling of human prostate tissues: insights into gene expression patterns of prostate development during puberty.

Goodman F. Limb malformations and the human HOX genes. Maeda Y. Transcriptional control of lung morphogenesis. Shah N. These genes were first discovered in the fruit fly Drosophila 22 and identified as genes whose mutations cause body segment transformation, also known as homeotic transformation.

This phenomenon consists of the transformation of one part of the body into another, e. Homeobox family of genes encodes regulatory proteins controlling basic developmental processes in several tissues, including orofacial tissues They contain a common nucleotide sequence homeobox coding for specific nuclear proteins homeoproteins that act as transcription factors.

The homeobox sequence encodes a aminoacid domain, the homeodomain, responsible for DNA binding 8,11, Structural analyses have shown that the homeodomain consists of a helix-turn-helix motif that binds the DNA by inserting the recognition helix into the major groove of the DNA and its amino-terminal arm into the adjacent minor groove The specificity of this binding allows homeoproteins to activate or repress the expression of batteries of downstream target genes The homeobox were shown to occur in all Metazoa, ranging from sponges to vertebrates and also plants and fungi 6.

This review aims at introducing readers to some of the homeobox family functions in normal tissues and especially in cancer development, which could be of valuable clinical interest in the near future. The family of vertebrate homeobox genes can be divided in two subfamilies: a the clustered homeobox genes, known as HOX genes or class I; and b the nonclustered, or divergent homeobox genes. The HOX family plays a fundamental role in the morphogenesis of vertebrate embryo cells, providing regional information along the main body axis 11, HOX genes have been reported as implicated in angiogenesis and wound repair 36 , in functions of the female reproductive tract 35 , and in pulmonary hypertension and emphysema Mutations in HOX genes may yet participate in human malformations, e.

Also, Ingram et al. The nonclustered genes are a large number of genes scattered throughout the genome that, nevertheless, can be organized in distinct families based on their homologies and functional similarities.

During the last decades, several homeobox genes, clustered and nonclustered, were identified in normal tissue, in malignant cells, and in different diseases and metabolic alterations 7. PAX genes are the homeobox family with the strongest connections with human diseases. PAX2 has been implicated in breast cancer 34 , renal hypoplasia and renal disease 26 ; PAX3 has a role in rhabdomyosarcomas 2 and melanomas 31 ; PAX5 determines the identity of B cells MSX homeobox genes are involved in the normal teeth development and in familial teeth agenesis 9.

Oral cancer is, respectively, the fifth and seventh most common cancer for male and female in the general population. About half of the patients afflicted will die within five years of diagnosis During the last decade, much progress has been made in delineating the molecular alterations that lead to oncogenic transformation Several studies indicate that alcohol and tobacco use are important factors causing oral cancer 19, A genetic predisposition has been suggested, since the majority of the population exposed to the mentioned risk factors does not develop oral cancer.

Also, sporadic cases of oral cancer occur in young adults, non-users of any identifiable carcinogen, and there have been reports of family history involvement Today, many genetic events caused by chromosomal alterations or mutations have been proposed to underline the progression of oral tumors The development regulatory genes 4,11 are an important group of genes involved with carcinogenesis. These genes were never associated with oral cancer.

Recently, we were able to show that four distinct squamous cell carcinoma cell lines express HOX genes differently from the control cells and tissue Cancer and normal development have a great deal in common, as both processes involve shifts between cell proliferation and differentiation 4. Recent research has demonstrated that improper regulation of development genes may result in cancer. However, there is a lot to be learned about the interplay that exists between development, cell cycle, apoptosis and cancer.

Many cancers exhibit expression or alteration in homeobox genes. They include leukemia, colon, skin, prostate, breast and ovary cancers, among others. Recently it was shown that loss of expression in human breast cancer of p53, a gene that protects cells against malignant transformation, may be primarily due to lack of expression of HOXA5 However, the precise mechanisms by which homeobox gene alterations lead to cancer are still unknown The demonstration of cell lineage-specific patterns of HOX gene activation in human and murine leukemic cell lines supports the hypothesis that HOX gene expression can regulate normal hematopoietic differentiation A genomic fusion in frame between the nucleoporin gene NUP98 and the HOXA9 gene was shown in three patients with myeloid leukemia and translocation t 7;11 Chimeric fusion proteins resulting from the transcription activator domain of one protein and the DNA binding domain of another display a high oncogenic potential.

The locus HOXC is mainly implicated in lymphomas. Major differences in HOX gene expression are detectable in primary solid tumors kidney, colon, breast, prostate and smal cell lung cancer compared with the corresponding normal adult organs 7, Misexpression of HOX genes is detectable in metastatic lesions related to the primary tumor of origin and the corresponding normal tissue, supporting the hypothesis of an implication of homeoproteins in cancer evolution