Hox genes, clusters and collinearity

2018 ◽  
Vol 62 (11-12) ◽  
pp. 659-663 ◽  
Author(s):  
Robb Krumlauf
Keyword(s):  
Gene Family ◽  
Evolutionary Biology ◽  
Hox Genes ◽  
Gene Clusters ◽  
Regulatory Mechanisms ◽  
Homeotic Gene ◽  
Gene Complex ◽  
40Th Anniversary ◽  
Hox Gene ◽  
Conserved Gene

This year marks the 40th anniversary of the discovery by Ed Lewis of the property of collinearity in the bithorax gene complex in Drosophila. This landmark work illustrated the need to understand regulatory mechanisms that coordinate expression of homeotic gene clusters. Through the efforts of many groups, investigation of the Hox gene family has generated many fundamental findings on the roles and regulation of this conserved gene family in development, disease and evolution. This has led to a number of important conceptual advances in gene regulation and evolutionary biology. This article presents some of the history and advances made through studies on Hox gene clusters.

Hox cluster genes and collinearities throughout the tree of animal life

2018 ◽  
Vol 62 (11-12) ◽  
pp. 673-683 ◽  
Author(s):  
Stephen J. Gaunt
Keyword(s):  
Evolutionary Biology ◽  
Hox Genes ◽  
Gene Clusters ◽  
The Body ◽  
Last Common Ancestor ◽  
Major Step ◽  
Hox Cluster ◽  
Cluster Function ◽  
And Function ◽  
Novel Structures

The discovery of Hox gene clusters, first in Drosophila (a protostome) and then as homologues in vertebrates (deuterostomes), was a major step in our understanding of both developmental and evolutionary biology. Hox genes in both species perform the same overall function: that is, organization of the body along its head-tail axis. The conclusion is that the protostome-deuterostome ancestor, founder of 99% of all described animal species, must already have had this same basic Hox cluster, and that it probably used it in the same way to establish its body plan. A striking feature of Hox genes is the spatial collinearity rule: that order of the genes along the chromosome corresponds with the order of their expression domains along the embryo. For vertebrates, though not Drosophila, there is also the temporal collinearity rule: that order of genes along the chromosome corresponds with timing of Hox expressions in the embryo. Although Hox genes are clearly recognized in pre-bilaterians (Cnidaria), it is only in bilaterians that the characteristic clustered Hox arrangement and function is commonly found. Spatial collinearity in expression is conserved widely throughout Bilateria but temporal collinearity is so far limited to vertebrates, cephalochordates, and some arthropods and annelids. In addition to conserved use of Hox genes to pattern the head-tail axis, some animal groups, particularly lophotrochozoans, have extensively co-opted Hox genes, outside collinearity rules, to regulate development of novel structures. Satisfactory understanding of Hox cluster function requires better understanding of the bilaterian last common ancestor (Urbilateria). Xenacoelomorpha may provide useful living models of the ancestral bilaterian condition.

The CALM/AF10 Fusion: Molecular Analysis of the Fusion Transcripts in 13 Cases of AML and ALL; Gene Expression Profiling Reveals HOX Gene Deregulation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2895-2895 ◽  
Author(s):  
Alexandre Krause ◽  
Alexander Kohlmann ◽  
Torsten Haferlach ◽  
Claudia Schoch ◽  
Susanne Schnittger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fusion Protein ◽  
Hox Genes ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Gene Clusters ◽  
Dominant Negative ◽  
Nucleotide Position ◽  
Gamma Delta ◽  
Hox Gene

Abstract The t(10;11)(p13;q14) is a recurring translocation associated with the CALM/AF10 fusion gene which is found in undifferentiated leukemia, acute myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma with poor prognosis. The CALM/AF10 fusion protein was reported to be the most common fusion protein in T-ALL with TCR gamma delta rearrangement. We have analyzed samples from 9 patients with different types of leukemia: case 1 (AML M2), case 2 (AML M0), case 3 (Pre T-ALL), case 4 (Acute Undifferentiated Leukemia), case 5 (PreT-ALL), case 6 and 7 (ProT-ALL), case 8 (T-ALL), case 9 (AML), with a t(10;11) translocation suggesting a CALM/AF10-rearrangement. The samples were analyzed for the presence of the CALM/AF10 and AF10/CALM mRNA by RT-PCR and sequence analysis. All these patients were found positive for the CALM/AF10 fusion. In addition, we analyzed a series of twenty-nine patients with T-ALL with gamma delta rearrangement. Among these patients, four were positive for CALM/AF10 transcripts, indicating a high incidence of CALM/AF10 fusions in this group of leukemia. We found three different breakpoints in CALM at nucleotide 1926, 2091 and a new exon, with 106 bases inserted after nt 2064 of CALM in patient 4. In AF10 four breakpoints were identified: at nucleotide position 424, 589, 883 and 979. In seven patients it was also possible to amplify the reciprocal AF10/CALM fusion transcript (case 1, 3, 4, 8, 9, 10 and 11). There was no correlation between disease phenotype and breakpoint location. The patients were 5 to 46 years old (median 25). Ten CALM/AF10 positive patients were further analyzed using oligonucleotide microarrays representing 33,000 different genes (U133 set, Affymetrix). Analysis of microarray gene expression signatures of these patients revealed high expression levels of the homeobox gene MEIS1 and the HOXA cluster genes HOXA1, HOXA4, HOXA5, HOXA7, HOXA9, and HOXA10. The overexpression of HOX genes seen in these CALM/AF10 positive leukemias is reminiscent of the pattern seen in leukemias with rearrangements of the MLL gene, and complex aberrant karyotypes suggesting a common effector pathway (i.e. HOX gene deregulation) for these diverse leukemias. It is known that alhambra, the Drosophila homologue of AF10 can act on polycomb group responsive elements, which play a critical role in the regulation of the HOX gene clusters. It is thus conceivable that the CALM/AF10 fusion proteins acts in a dominant negative fashion on wild type AF10 function relieving the repression that is presumably normally exerted by AF10 on the expression of HOX genes.

scholarly journals Rapid genomic DNA variation in newly hybridized carp lineages derived from Cyprinus carpio (♀) × Megalobrama amblycephala (♂)

2019 ◽  
Author(s):  
Kaikun Luo ◽  
Shi Wang ◽  
Yeqing Fu ◽  
Pei Zhou ◽  
Xuexue Huang ◽  
...  
Keyword(s):  
Common Carp ◽  
Genomic Dna ◽  
First Generation ◽  
Second Generation ◽  
Hox Genes ◽  
Gene Clusters ◽  
Megalobrama Amblycephala ◽  
Distant Hybridization ◽  
Hox Gene ◽  
Blunt Snout Bream

Abstract Background: Distant hybridization can generate changes in phenotypes and genotypes that lead to the formation of new hybrid lineages with genetic variation. In this study, based on the establishment of two bisexual fertile carp lineages, including the improved diploid common carp (IDC) lineage and the improved diploid scattered mirror carp (IDMC) lineage, from the interspecific hybridization of common carp (Cyprinus carpio, 2n = 100) (♀) × blunt snout bream (Megalobrama amblycephala, 2n = 48) (♂), provided a good platform to investigate the relationship of genetic and variation between the parents and their hybrid progenies. Result: In this study, we investigated the genetic variation of 12 Hox genes in the two types of carp lineages derived from common carp (♀) × blunt snout bream (♂). Hox gene clusters were abundant in the first generation of IDC, but most were not stably inherited in the second generation. In contrast, we did not find obvious mutations in Hox genes in the first generation of IDMC, and almost all the Hox gene clusters were stably inherited from the first generation to the second generation of IDMC. Interestingly, we found obvious recombinant clusters of Hox genes in both carp lineages, and partially recombinant clusters of Hox genes were stably inherited from the first generation to the second generation in both types of carp lineages. On the other hand, some Hox genes were gradually becoming pseudogenes, and some genes were completely pseudogenised in IDC or IDMC. Conclusions: Our results provided important evidence that distant hybridization produces rapid genomic DNA changes that may or may not be stably inherited, providing novel insights into the function of hybridization in the establishment of improved lineages used as new fish resources for aquaculture.

HOX Genes - Candidate Tumor Suppressor Genes in Adult and Childhood Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2641-2641
Author(s):  
Gordon R. Strathdee ◽  
Tessa L. Holyoake ◽  
Alyson Sim ◽  
Anton Parker ◽  
David G. Oscier ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Gene Family ◽  
Tumor Suppressor Genes ◽  
Poor Prognosis ◽  
Childhood Leukemia ◽  
Hox Genes ◽  
Blast Crisis ◽  
Family Members ◽  
Hox Gene

Abstract The role of the HOX gene family in leukemia development has been extensively studied. However, these studies have focused almost exclusively on the potential oncogenic role of HOX gene family members. In contrast to the oncogenic function often attributed to HOX genes, our studies have identified several HOX gene family members as candidate tumor suppressor genes and shown that inactivation of HOX genes, particularly HOXA4, is associated with poor prognosis. We have used multiple quantitative methylation assays to search for epigenetic inactivation of HOX genes in adult and childhood leukemia. In both adult myeloid and lymphoid leukemia two members of the HOXA cluster (HOXA4 and A5) were found to be frequently inactivated by promoter hypermethylation (26–64% of cases were hypermethylated). In contrast, a further 12 HOXA, B and C cluster genes were found to be essentially devoid of hypermethylation (except HOXA6 in CLL, where 34% of samples exhibited hypermethylation). HOXA4 and HOXA5 were also frequently inactivated in childhood ALL and AML (39–79% of samples). However, in contrast to the adult leukemias, all but one of the additional HOX genes analyzed were also found to be targets for hypermethylation in both ALL and AML (4–26% of samples), suggesting that HOX genes are differentially regulated in childhood versus adult leukemia. Hypermethylation of HOX genes (HOXA4, HOXA5 and HOXA6) was associated with loss of expression of the corresponding gene. Expression analysis also suggests that interaction between different HOX genes may be crucial. In normal karyotype AML samples, those expressing of high levels of HOXA9, but not those with low HOXA9 expression, were associated with invariable HOXA4 hypermethylation (p=0.01). Interestingly HOXA4 hypermethylation also correlates with poor prognosis in all types of leukemia tested. Hypermethylation of HOXA4 correlates with progression to blast crisis (p=0.007) and poor response to imatinib in CML (p=0.04), with cytogenetic status in AML (33%, 72% and 100% in good, intermediate and poor prognostic groups respectively, p=0.0004) and with IgVh mutational status (p=0.003) and poor survival in CLL (median survival 159 versus 199 months in hypermethylated and non hypermethylated patients, respectively). Furthermore transfection of a HOXA4 expressing construct into a CML blast crisis cell line results in re-expression of markers of myeloid differentiation, suggesting that loss of HOXA4 is functionally relevant in leukemic cells. These results indicate that aberrant epigenetic regulation of HOXA4, and indeed other frequently inactivated HOX genes such as HOXA5 and HOXA6, may play a key role in the development of multiple types of leukemia. Thus co-ordinated up and down regulation of expression of HOX gene family members may be crucial in the leukemogenic process.

scholarly journals Hox Gene Collinearity May Be Related to Noether Theory on Symmetry and Its Linked Conserved Quantity

J ◽  
2020 ◽  
Vol 3 (2) ◽  
pp. 151-161
Author(s):  
Spyros Papageorgiou
Keyword(s):  
Hox Genes ◽  
Fundamental Property ◽  
Gene Clusters ◽  
Strand Break ◽  
Early Embryo ◽  
Conserved Quantity ◽  
Biophysical Model ◽  
Self Similarity ◽  
Hox Gene ◽  
Hox Clusters

Hox Gene Collinearity (HGC) is a fundamental property that controls the development of many animal species, including vertebrates. In the Hox gene clusters, the genes are located in a sequential order Hox1, Hox2, Hox3, etc., along the 3’ to 5’ direction of the cluster in the chromosome. During Hox cluster activation, the Hox genes are expressed sequentially in the ontogenetic units D1, D2, D3, etc., along the anterior–posterior axis (A-P) of the early embryo. This collinearity, first observed by E.B. Lewis, is surprising because the spatial collinearity of these structures (Hox clusters and embryos) correlates entities that differ by about four orders of magnitude. Biomolecular mechanisms alone cannot explain such correlations. Long-range physical interactions, such as diffusion or electric attractions, should be involved. A biophysical model (BM) was formulated, which, in alignment with the biomolecular processes, successfully describes the existing vertebrate genetic engineering data. One hundred years ago, Emmy Noether made a fundamental discovery in mathematics and physics. She proved, rigorously, that a physical system obeying a symmetry law (e.g., rotations or self-similarity) is followed by a conserved physical quantity. It is argued here that HGC obeys a ‘primitive’ self-similarity symmetry. In this case, the associated primitive conserved quantity is the irreversibly increasing ‘ratchet’-like Hoxgene ordering where some genes may be missing. The genes of a vertebrate Hox clusterare located along a finite straight line. The same order follows the ontogenetic unitsof the vertebrate embryo. Therefore, HGC is a manifestation of a primitive Noether Theory (NT). NT may be applied to other than the vertebrate case, for instance, to animals with a circular topological symmetry. For example, the observed abnormal Hox gene ordering of the echinoderm Hox clusters may be reproduced by a double-strand break of the circular Hox gene ordering and its subsequent incorporation in the flanking chromosome.

scholarly journals HOX Gene Aberrant Expression in Skin Melanoma: A Review

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Gérald E. Piérard ◽  
Claudine Piérard-Franchimont
Keyword(s):  
Protein Interactions ◽  
Hox Genes ◽  
Tumour Progression ◽  
Gene Clusters ◽  
Skin Melanoma ◽  
Protein Protein Interactions ◽  
Cell Nuclei ◽  
Aberrant Expression ◽  
Hox Gene ◽  
Hox Protein

The homeobox family and its subset of HOX gene products represent a family of transcription factors directing DNA-protein and protein-protein interactions. In the embryo, they are central regulators in cell differentiation during morphogenesis. A series of genes of the four HOX gene clusters A, B, C, and D were reported to show aberrant expressions in oncogenesis, particularly in cutaneous malignant melanoma (CMM). They are involved in cell proliferation and progression in the CMM metastatic path. We present relevant peer-reviewed literature findings about the aberrant expression of HOX genes in CMM. The number of CMM cell nuclei exhibiting aberrant HOX protein expression appears correlated with tumour progression.

scholarly journals Hox Gene Collinearity May Be Related to Noether’s Theory on Symmetry and Its Linked Conserved Quantities

2019 ◽  
Author(s):  
Spyros Papageorgiou
Keyword(s):  
Hox Genes ◽  
Fundamental Property ◽  
Gene Clusters ◽  
Early Embryo ◽  
Biophysical Model ◽  
Self Similarity ◽  
Hox Gene ◽  
Hox Cluster ◽  
Straight Line ◽  
Physical Interactions

Hox Gene Collinearity (HGC) is a fundamental property that determines the development of many animal clades including Vertebrates. In the Hox gene clusters the genes are located in a sequence Hox1, Hox2, Hox3,… along the 3’ to 5’ direction of the cluster in the chromosome. During Hox cluster activation the Hox genes are expressed sequentially in the ontogenetic units D1, D2, D3,… along the anterior (A)- Posterior (P) axis of the early embryo. This collinearity, first observed by E.B. Lewis, is surprising because the spatial extent of these structures (Hox clusters and embryos) differ by about 4 orders of magnitude. Biomolecular mechanisms alone cannot explain this correlation. Long range physical interactions like diffusion or electric attractions should be involved. A biophysical model (BM) has been  formulated which cooperates with the biomolecular processes and describes the data successfully. Hundred years ago E. Noether made a fundamental discovery in Mathematics and Physics. She proved rigorously that a physical system obeying a symmetry law (e.g.rotations or self similarity) is linked to a conserved physical quantity. It is argued here that HGC obeys a ‘primitive’ self similarity symmetry of the genes of a Hox cluster along a finite straight line. In the case of Vertebrates, the associated partially conserved quantity is the ever increasing ‘ratchet’- like gene ordering where some Hox genes are missing. Another application of Noether’s Theory is performed to rotationally symmetric embryos like the sea urchin.

Defined concentrations of a posteriorizing signal are critical for MafB/Kreisler segmental expression in the hindbrain

Development ◽  
1998 ◽  
Vol 125 (7) ◽  
pp. 1173-1181 ◽  
Author(s):  
A. Grapin-Botton ◽  
M.A. Bonnin ◽  
M. Sieweke ◽  
N.M. Le Douarin
Keyword(s):  
Gene Expression ◽  
Neural Crest ◽  
Leucine Zipper ◽  
Hox Genes ◽  
Paraxial Mesoderm ◽  
Regulatory Mechanisms ◽  
Expression Domain ◽  
Environmental Signals ◽  
Hox Gene ◽  
Segmental Expression

It has been shown by using the quail/chick chimera system that Hox gene expression in the hindbrain is influenced by positional signals arising from the environment. In order to decipher the pathway that leads to Hox gene induction, we have investigated whether a Hox gene regulator, the leucine zipper transcription factor MafB/Kr, is itself transcriptionally regulated by the environmental signals. This gene is normally expressed in rhombomeres (r) 5 and 6 and their associated neural crest. MafB/Kr expression is maintained in r5/6 when grafted into the environment of r3/4. On the contrary, the environment of rhombomeres 7/8 represses MafB/Kr expression. Thus, as previously shown for the expression of Hox genes, MafB/Kr expression is regulated by a posterior-dominant signal, which in this case induces the loss of expression of this gene. We also show that the posterior signal can be transferred to the r5/6 neuroepithelium by posterior somites (somites 7 to 10) grafted laterally to r5/6. At the r4 level, the same somites induce MafB/Kr in r4, leading it to behave like r5/6. The posterior environment regulates MafB/Kr expression in the neural crest as it does in the corresponding hindbrain level, showing that some positional regulatory mechanisms are shared by neural tube and neural crest cells. Retinoic acid beads mimic the effect produced by the somites in repressing MafB/Kr in r5/6 and progressively inducing it more rostrally as its concentration increases. We therefore propose that the MafB/Kr expression domain is defined by a molecule unevenly distributed in the paraxial mesoderm. This molecule would allow the expression of the MafB/Kr gene in a narrow window of concentration by activating its expression at a definite threshold and repressing it at higher levels, accounting for its limited domain of expression in only two rhombomeres. It thus appears that the regulation of MafB/Kr expression in the rhombomeres could be controlled by the same posteriorizing factor(s) as Hox genes.

The evolving role of Hox genes in arthropods

Development ◽  
1994 ◽  
Vol 1994 (Supplement) ◽  
pp. 209-215
Author(s):  
Michael Akam ◽  
Michalis Averof ◽  
James Castelli-Gair ◽  
Rachel Dawes ◽  
Francesco Falciani ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Early Development ◽  
Hox Genes ◽  
Homeotic Gene ◽  
Homeotic Genes ◽  
Gene Duplications ◽  
Fushi Tarazu ◽  
Hox Gene ◽  
Hox Cluster

Comparisons between Hox genes in different arthropods suggest that the diversity of Antennapedia-class homeotic genes present in modern insects had already arisen before the divergence of insects and crustaceans, probably during the Cambrian. Hox gene duplications are therefore unlikely to have occurred concomitantly with trunk segment diversification in the lineage leading to insects. Available data suggest that domains of homeotic gene expression are also generally conserved among insects, but changes in Hox gene regulation may have played a significant role in segment diversification. Differences that have been documented alter specific aspects of Hox gene regulation within segments and correlate with alterations in segment morphology rather than overt homeotic transformations. The Drosophila Hox cluster contains several homeobox genes that are not homeotic genes – bicoid, fushi-tarazu and zen. The role of these genes during early development has been studied in some detail. It appears to be without parallel among the vertebrate Hox genes. No well conserved homologues of these genes have been found in other taxa, suggesting that they are evolving faster than the homeotic genes. Relatively divergent Antp-class genes isolated from other insects are probably homologues of fushi-tarazu, but these are almost unrecognisable outside of their homeodomains, and have accumulated approximately 10 times as many changes in their homeodomains as have homeotic genes in the same comparisons. They show conserved patterns of expression in the nervous system, but not during early development.

scholarly journals Role of HOX Genes in Stem Cell Differentiation and Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Seema Bhatlekar ◽  
Jeremy Z. Fields ◽  
Bruce M. Boman
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Hox Genes ◽  
Stem Cell Differentiation ◽  
Gene Clusters ◽  
Bilateral Symmetry ◽  
The Cancer Genome Atlas ◽  
Cancer Development ◽  
Hox Gene

HOX genes encode an evolutionarily conserved set of transcription factors that control how the phenotype of an organism becomes organized during development based on its genetic makeup. For example, in bilaterian-type animals, HOX genes are organized in gene clusters that encode anatomic segment identity, that is, whether the embryo will form with bilateral symmetry with a head (anterior), tail (posterior), back (dorsal), and belly (ventral). Although HOX genes are known to regulate stem cell (SC) differentiation and HOX genes are dysregulated in cancer, the mechanisms by which dysregulation of HOX genes in SCs causes cancer development is not fully understood. Therefore, the purpose of this manuscript was (i) to review the role of HOX genes in SC differentiation, particularly in embryonic, adult tissue-specific, and induced pluripotent SC, and (ii) to investigate how dysregulated HOX genes in SCs are responsible for the development of colorectal cancer (CRC) and acute myeloid leukemia (AML). We analyzed HOX gene expression in CRC and AML using information from The Cancer Genome Atlas study. Finally, we reviewed the literature on HOX genes and related therapeutics that might help us understand ways to develop SC-specific therapies that target aberrant HOX gene expression that contributes to cancer development.

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