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Endometrial cancer (UCEC) is one of three major malignant tumors in women. The HOX gene regulates tumor development. However, the potential roles of HOX in the expression mechanism of multiple cell types and in the development and progression of tumor microenvironment (TME) cell infiltration in UCEC remain unknown. In this study, we utilized both the The Cancer Genome Atlas (TCGA) database and International Cancer Genome Consortium (ICGC) database to analyze transcriptome data of 529 patients with UCEC based on 39 HOX genes, combing clinical information, we discovered HOX gene were a pivotal factor in the development and progression of UCEC and in the formation of TME diversity and complexity. Here, a new scoring system was developed to quantify individual HOX patterns in UCEC. Our study found that patients in the low HOX score group had abundant anti-tumor immune cell infiltration, good tumor differentiation, and better prognoses. In contrast, a high HOX score was associated with blockade of immune checkpoints, which enhances the response to immunotherapy. The Real-Time quantitative PCR (RT-qPCR) and Immunohistochemistry (IHC) exhibited a higher expression of the HOX gene in the tumor patients. We revealed that the significant upregulation of the HOX gene in the epithelial cells can activate signaling pathway associated with tumour invasion and metastasis through single-cell RNA sequencing (scRNA-seq), such as nucleotide metabolic proce and so on. Finally, a risk prognostic model established by the positive relationship between HOX scores and cancer-associated fibroblasts (CAFs) can predict the prognosis of individual patients by scRNA-seq and transcriptome data sets. In sum, HOX gene may serve as a potential biomarker for the diagnosis and prediction of UCEC and to develop more effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

The vertebral column is a characteristic structure of vertebrates. Genetic studies in mice have shown that Hox-mediated patterning plays a key role in specifying discrete anatomical regions of the vertebral column. Expression pattern analyses in several vertebrate embryos have provided correlative evidence that the anterior boundaries of Hox expression coincide with distinct anatomical vertebrae. However, because functional analyses have been limited to mice, it remains unclear which Hox genes actually function in vertebral patterning in other vertebrates. In this study, various zebrafish Hox mutants were generated for loss-of-function phenotypic analysis to functionally decipher the Hox code responsible for the zebrafish anterior vertebrae between the occipital and thoracic vertebrae. We found that Hox genes in HoxB- and HoxC-related clusters participate in regulating the morphology of the zebrafish anterior vertebrae. In addition, medaka hoxc6a was found to be responsible for anterior vertebral identity, as in zebrafish. Based on phenotypic similarities with Hoxc6 knockout mice, our results suggest that the Hox patterning system, including at least Hoxc6, may have been functionally established in the vertebral patterning of the common ancestor of ray-finned and lobe-finned fishes. [ABSTRACT FROM AUTHOR]

Abstract Endometrial cancer (UCEC) is one of three major malignant tumors in women. The HOX gene regulates tumor development. However, the potential roles of HOX in the expression mechanism of multiple cell types and in the development and progression of tumor microenvironment (TME) cell infiltration in UCEC remain unknown. In this study, we utilized both the The Cancer Genome Atlas (TCGA) database and International Cancer Genome Consortium (ICGC) database to analyze transcriptome data of 529 patients with UCEC based on 39 HOX genes, combing clinical information, we discovered HOX gene were a pivotal factor in the development and progression of UCEC and in the formation of TME diversity and complexity. Here, a new scoring system was developed to quantify individual HOX patterns in UCEC. Our study found that patients in the low HOX score group had abundant anti-tumor immune cell infiltration, good tumor differentiation, and better prognoses. In contrast, a high HOX score was associated with blockade of immune checkpoints, which enhances the response to immunotherapy. The Real-Time quantitative PCR (RT-qPCR) and Immunohistochemistry (IHC) exhibited a higher expression of the HOX gene in the tumor patients. We revealed that the significant upregulation of the HOX gene in the epithelial cells can activate signaling pathway associated with tumour invasion and metastasis through single-cell RNA sequencing (scRNA-seq), such as nucleotide metabolic proce and so on. Finally, a risk prognostic model established by the positive relationship between HOX scores and cancer-associated fibroblasts (CAFs) can predict the prognosis of individual patients by scRNA-seq and transcriptome data sets. In sum, HOX gene may serve as a potential biomarker for the diagnosis and prediction of UCEC and to develop more effective therapeutic strategies.

The chromosomally-arrayed Hox gene family plays central roles in embryonic patterning and the specification of cell identities throughout the animal kingdom. In vertebrates, the relatively large number of Hox genes and pervasive expression throughout the body has hindered understanding of their biological roles during differentiation. Studies on the subtype diversification of spinal motor neurons (MNs) have provided a tractable system to explore the function of Hox genes during differentiation, and have provided an entry point to explore how neuronal fate determinants contribute to motor circuit assembly. Recent work, using both in vitro and in vivo models of MN subtype differentiation, have revealed how patterning morphogens and regulation of chromatin structure determine cell-type specific programs of gene expression. These studies have not only shed light on basic mechanisms of rostrocaudal patterning in vertebrates, but also have illuminated mechanistic principles of gene regulation that likely operate in the development and maintenance of terminal fates in other systems. [ABSTRACT FROM AUTHOR]

Homeobox (HOX) genes encode highly conserved transcription factors that play vital roles in embryonic development. DNA methylation is a pivotal regulatory epigenetic signaling mark responsible for regulating gene expression. Abnormal DNA methylation is largely associated with the aberrant expression of HOX genes, which is implicated in a broad range of human diseases, including cancer. Numerous studies have clarified the mechanisms of DNA methylation in both physiological and pathological processes. In this review, we focus on how DNA methylation regulates HOX genes and briefly discuss drug development approaches targeting these mechanisms.

Hox genes encode transcription factors that are crucial regulators of various developmental processes, including patterning of the body axis and differentiation of cells, tissues and organs. They are organized in clusters in a wide range of Metazoans and expressed during embryonic development in a collinear manner from the 3′ to the 5′ end of these genomic units. Hox genes are part of the larger homeobox gene super-class, and other gene clusters beyond Hox are being increasingly discovered. This transcriptional dynamic generates spatiotemporal expression patterns throughout the developing body that are required for the establishment of fields of cell identity. Here we suggest that subcluster temporal collinearity may occur during the development of a bivalve species, as demonstrated for other Bilateran species. We performed a genome-wide analysis of the Mytilus coruscus Hox gene family, including gene structure, synteny, and expression patterns. It was shown that 11 Hox genes were evenly distributed within one chromosome in M. coruscus. Phylogenetic analysis showed that 11 Hox proteins were divided into four groups and each of them contained different conserved motifs. Besides, sequence alignment and analysis showed the conservation of 11 Hox genes of M. coruscus. Selection pressure analysis revealed the Ka/Ks ratios of Hox1, Hox4, Lox4, Post2, and Post1 were less than 1 in Bivalvia, indicating that these five Hox genes suffered significant purifying selection. Notably, Hox1, Hox4, Post2 were overlapped with the leading gene in the subcluster collinearity. This discovery suggests the potential existence of subcluster temporal collinearity in M. coruscus, which adds new insights into Hox gene organization in Bivalvia or Mollusca.

Background: Homeodomain protein transforming growth factor beta-induced factor 2 like, X-linked (TGIF2 LX) has been demonstrated to act as a transcription factor and regulate cancer cell proliferation. Long non-coding RNAs (lncRNAs) are well known as molecular regulators of colorectal cancer (CRC). Our aim was to evaluate the clinical and biological significance of TGIF2 LX and its effect on lncRNAs regulator of reprogramming (ROR) and X-inactive specific transcript (XIST) expression in CRC cells. Materials and Methods: Thirty-six CRC tissues and 22 adjacent normal colorectal tissues were subjected to RNA extraction and analysis of TGIF2 LX gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). The human SW1116 cell line was transfected with cDNA for the TGIF2 LX gene. Microscopic analysis, reverse transcriptase PCR, and western blotting were used for confirming at transcriptional and translational levels. Methyl thiazolyl tetrazolium and colony formation assays were applied for evaluating the in vitro cell viability and colony-forming ability, respectively. LncRNA expression analysis was carried out using qRT-PCR. Results: The results showed that the expression levels of TGIF2 LX were significantly downregulated in CRC tissues compared to adjacent normal tissues (P = 0.032). Furthermore, the overexpression of TGIF2 LX could reduce the CRC cell line proliferation. The gene expression analysis revealed a significantly reduced level of lncRNA ROR and lncRNA XIST in TGIF2 LX-transfected SW1116 cells compared to nontransfected cells. Conclusion: Our findings provided evidence of molecular mechanisms by which TGIF2 LX may interact with lncRNAs ROR and XSIST to regulate CRC development by acting as a tumor suppressor. Thus, this protein may potentially be a promising option for CRC gene-based therapeutic strategies. [ABSTRACT FROM AUTHOR]

In many bilaterians, Hox genes are generally clustered along the chromosomes and expressed in spatial and temporal order. In vertebrates, the expression of Hox genes follows a whole-cluster spatio-temporal collinearity (WSTC) pattern, whereas in some invertebrates the expression of Hox genes exhibits a subcluster-level spatio-temporal collinearity pattern. In bilaterians, the diversity of collinearity patterns and the cause of collinearity differences in Hox gene expression remain poorly understood. Here, we investigate genomic organization and expression pattern of Hox genes in the echiuran worm Urechis unicinctus (Annelida, Echiura). Urechis unicinctus has a split cluster with four subclusters divided by non-Hox genes: first subcluster (Hox1 and Hox2), second subcluster (Hox3), third subcluster (Hox4, Hox5, Lox5, Antp and Lox4), fourth subcluster (Lox2 and Post2). The expression of U. unicinctus Hox genes shows a subcluster-based whole-cluster spatio-temporal collinearity (S-WSTC) pattern: the anterior-most genes in each subcluster are activated in a spatially and temporally colinear manner (reminiscent of WSTC), with the subsequent genes in each subcluster then being very similar to their respective anterior-most subcluster gene. Combining genomic organization and expression profiles of Hox genes in different invertebrate lineages, we propose that the spatio-temporal collinearity of invertebrate Hox is subcluster-based. [ABSTRACT FROM AUTHOR]

The vertebral column is a characteristic structure of vertebrates. Genetic studies in mice have shown that Hox-mediated patterning plays a key role in specifying discrete anatomical regions of the vertebral column. Expression pattern analyses in several vertebrate embryos have provided correlative evidence that the anterior boundaries of Hox expression coincide with distinct anatomical vertebrae. However, because functional analyses have been limited to mice, it remains unclear which Hox genes actually function in vertebral patterning in other vertebrates. In this study, various zebrafish Hox mutants were generated for loss-of-function phenotypic analysis to functionally decipher the Hox code responsible for the zebrafish anterior vertebrae between the occipital and thoracic vertebrae. We found that Hox genes in HoxB- and HoxC-related clusters participate in regulating the morphology of the zebrafish anterior vertebrae. In addition, medaka hoxc6a was found to be responsible for anterior vertebral identity, as in zebrafish. Based on phenotypic similarities with Hoxc6 knockout mice, our results suggest that the Hox patterning system, including at least Hoxc6, may have been functionally established in the vertebral patterning of the common ancestor of ray-finned and lobe-finned fishes., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Finger length ratios are organized during embryonic development of fingers as they exposed to sex steroid hormones, and may show varying degrees of sexual dimorphism between males and females in different animal groups. Among all the finger length ratios calculated in a sample, the ratio between the second to fourth fingers (2D: 4D) is the most important one. In this study, the 2D:4D ratios in both sides of the body (right and left) in all limbs were investigated to determine if sexual dimorphism is present in the 2D: 4D ratios in 44 specimens studied (20 males and 24 females) of Acanthodactylus blanfordi. Other morphological traits of the two sexes were also examined (23 metric and meristic traits), as a result, sexual dimorphism was observed in five metric and meristic morphological traits. In terms of the ratio of the size of the fingers and toes, sexual dimorphism in the length of the fingers was observed only in 2D: 4D on the right side of the body in forelimbs and hindlimbs. The value of this trait was higher in males than females and this difference was statistically significant P ≤0.05).

Differentiation of oligodendroglial progenitor cells (OPCs) into myelinating oligodendrocytes is known to be regulated by the microenvironment where they differentiate. However, current research has not verified whether or not oligodendroglial lineage cells (OLCs) derived from different anatomical regions of the central nervous system (CNS) respond to microenvironmental cues in the same manner. Here, we isolated pure OPCs from rat neonatal forebrain (FB) and spinal cord (SC) and compared their phenotypes in the same in vitro conditions. We found that although FB and SC OLCs responded differently to the same external factors; they were distinct in proliferation response to mitogens, oligodendrocyte phenotype after differentiation, and cytotoxic responses to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type glutamate receptor-mediated excitotoxicity at immature stages of differentiation in a cell-intrinsic manner. Moreover, transcriptome analysis identified genes differentially expressed between these OPC populations, including those encoding transcription factors (TFs), cell surface molecules, and signaling molecules. Particularly, FB and SC OPCs retained the expression of FB- or SC-specific TFs, such as Foxg1 and Hoxc8, respectively, even after serial passaging in vitro. Given the essential role of these TFs in the regional identities of CNS cells along the rostrocaudal axis, our results suggest that CNS region-specific gene regulation by these TFs may cause cell-intrinsic differences in cellular responses between FB and SC OLCs to extracellular molecules. Further understanding of the regional differences among OPC populations will help to improve treatments for demyelination in different CNS regions and to facilitate the development of stem cell-derived OPCs for cell transplantation therapies for demyelination. Cover Image for this issue: doi. 10.1111/jnc.13809.

Long noncoding RNAs (lncRNAs) have been implicated in a variety of processes in development, differentiation, and disease. In Drosophila melanogaster, the bithorax Hox cluster contains three Hox genes [Ultrabithorax (Ubx), abdominal-A, and Abdominal-B], along with a number of lncRNAs, most with unknown functions. Here, we investigated the function of a lncRNA, lncRNA:PS4 that originates in the second intron of Ubx and is transcribed in the antisense orientation to Ubx. The expression pattern of lncRNA:PS4 is complementary to Ubx in the thoracic primordia, and the lncRNA:PS4 coding region overlaps the location of the large insertion that causes the dominant homeotic mutation Contrabithorax-1 (UbxCbx-1), which partially transforms Drosophila wings into halteres via ectopic activation of Ubx. This led us to investigate the potential role of this lncRNA in regulation of Ubx expression. The UbxCbx-1 mutation dramatically changes the pattern of lncRNA:PS4, eliminating the expression of most lncRNA:PS4 sequences from parasegment 4 (where Ubx protein is normally absent) and ectopically activating lncRNA:PS4 at high levels in the abdomen (where Ubx is normally expressed). These changes, however, did not lead to changes in the Ubx embryonic transcription pattern. Targeted deletion of the two promoters of lncRNA:PS4 did not result in the change of Ubx expression in the embryos. In the genetic background of a UbxCbx-1 mutation, the lncRNA:PS4 mutation does slightly enhance the ectopic activation of Ubx protein expression in wing discs and also slightly enhances the wing phenotype seen in UbxCbx-1 heterozygotes. [ABSTRACT FROM AUTHOR]

Sexual dimorphism in the ratio of digits length is a morphological feature resulted from the interaction between sex hormones and prenatal Hox genes, the latter is known to control the development of both limbs and genitals. The status of this trend and ratios have been investigated in various animal groups, including humans, other mammals, birds, reptiles, and amphibians. In this study, the body length and sexual dimorphism in the second-to-fourth, second-to-third and third-to-fourth digit lengths ratios (i.e., 2D:3D, 2D:4D, 3D:4D) of left fore and hind limbs were investigated in 54 specimens of toads collected from the northern Iran, including Bufo viridis (16 males and 19 females) and Pelobates syriacus (10 males and 9 females). In addition, the body length of the studied specimens were recorded. The results showed that the average body length (SVL) of female individuals of Pelobates syriacus was higher than those in males, which was found to be statistically significant (P≤0.05). Meanwhile, the average body length (SVL) of female individuals of Bufo viridis was found to be higher than those in males, however, the difference was not statistically significant. No sexual dimorphism was detected in the second-to-fourth, second-to-third and third-to-fourth digit lengths ratios of left fore and hind limbs between the male and female undividuals of Bufo viridis. However, the second-to-fourth digit ratio (2D:4D) in Pelobates syriacus species were found to be significantly different (P=0.040) between the male and female individuals, as the ratio was higher in males than females. Therefore, it could be concluded that the sexual dimorphism in 2D:4D of Pelobates syriacus species is consistent with those in most amphibians and diapsids.

Polycomb repressive complexes (PRCs) 1 and 2 maintain stable cellular memories of early fate decisions by establishing heritable patterns of gene repression. PRCs repress transcription through histone modifications and chromatin compaction, but their roles in neuronal subtype diversification are poorly defined. We found that PRC1 is essential for the specification of segmentally restricted spinal motor neuron (MN) subtypes, while PRC2 activity is dispensable to maintain MN positional identities during terminal differentiation. Mutation of the core PRC1 component Ring1 in mice leads to increased chromatin accessibility and ectopic expression of a broad variety of fates determinants, including Hox transcription factors, while neuronal class-specific features are maintained. Loss of MN subtype identities in Ring1 mutants is due to the suppression of Hox-dependent specification programs by derepressed Hox13 paralogs (Hoxa13, Hoxb13, Hoxc13, Hoxd13). These results indicate that PRC1 can function in the absence of de novo PRC2-dependent histone methylation to maintain chromatin topology and postmitotic neuronal fate.

Introduction: Transforming growth factor-beta-induced factor X-linked (TGIF2LX) as a homeodomain protein and TGF-β corepressor, could regulate proliferation of some cancer cells including colorectal cancer by some signaling pathways. Small non-coding RNAs (microRNA; miRNA) are known as molecular regulators of colorectal cancer that are involved in the processes of cell growth, proliferation, differentiation and apoptosis. The aim of this study was to evaluate the biological significance of TGIF2LX protein and its effect on the expression of oncogenic miRNAs miR-34a, miR-20a and miR-21 in colorectal cancer cells SW1116. Methods: Human SW1116 cell line and cell line transfected with cDNA encoding TGIF2LX gene were cultured in RPMI 1640 medium under appropriate conditions. MTT assay was used to assess cell viability in vitro. After RNA extraction from all cell groups and cDNA synthesis, miRNA expression analysis was performed using qReal-time PCR technique. Results: The results showed that the increased expression of TGIF2LX could reduce the proliferation of SW1116 cell line. Gene expression analysis showed that increased expression of TGIF2LX could significantly reduce the expression level of miR-21 (P<0.038). However, the expression levels of miR-34a and miR-20a in SW1116 cells transfected with TGIF2LX did not show a significant change compared to non-transfected cells (P>0.05). Conclusion: Our findings provide evidence of molecular mechanisms that the homeodomain protein TGIF2LX can act as a tumor suppressor in colorectal cancer cells by reducing miR-21 expression. Therefore, this protein can potentially be considered as a promising option for gene-based therapeutic strategies in this cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Hox transcription factors are master regulators of animal development. Although highly conserved, they can contribute to the formation of novel biological characteristics when modified, such as during the generation of hybrid species, thus potentially serving as species-specific molecular markers. Here, we systematically studied the evolution of genomic sequences of Hox loci in an artificial allotetraploid lineage (4nAT, 4n = 200) derived from a red crucian carp (♀, RCC, 2n = 100) × common carp (♂, CC, 2n = 100) cross and its parents (RCC and CC). Results PCR amplification yielded 23 distinct Hox gene fragments from 160 clones in 4nAT, 22 fragments from 90 clones in RCC, and 19 fragments from 90 clones in CC. Sequence alignment of the HoxA3a and HoxC10a genes indicated both the inheritance and loss of paternal genomic DNA in 4nAT. The HoxA5a gene from 4nAT consisted of two subtypes from RCC and two subtypes from CC, indicating that homologous recombination occurred in the 4nAT hybrid genome. Moreover, 4nAT carried genomic pseudogenization in the HoxA10b and HoxC13a loci. Interestingly, a new type of HoxC9a gene was found in 4nAT as a hybrid sequence of CC and RCC by recombination in the intronic region. Conclusion The results revealed the influence of Hox genes during polyploidization in hybrid fish. The data provided insight into the evolution of vertebrate genomes and might be benefit for artificial breeding programs.

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, 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 genetic relationship 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 improved 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 improved carp lineages, and partially recombinant clusters of Hox genes were stably inherited from the first generation to the second generation in both types of improved 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.

The neuroblast timer genes hunchback, Krü ppel, nubbin and castor are expressed in temporal sequence in neural stem cells, and in corresponding spatial sequence along the Drosophila blastoderm. As canonical gap genes, hunchback and Krü ppel play a crucial role in insect segmentation, but the roles of nubbin and castor in this process remain ambiguous. We have investigated the expression and functions of nubbin and castor during segmentation in the beetle Tribolium. We show that Tc-hunchback, Tc-Krü ppel, Tc-nubbin and Tc-castor are expressed sequentially in the segment addition zone, and that Tc-nubbin regulates segment identity redundantly with two previously described gap/gap-like genes, Tc-giant and Tc-knirps. Simultaneous knockdown of Tc-nubbin, Tc-giant and Tc-knirps results in the formation of ectopic legs on abdominal segments. This homeotic transformation is caused by loss of abdominal Hox gene expression, likely due to expanded Tc-Krüppel expression. Our findings support the theory that the neuroblast timer series was co-opted for use in insect segment patterning, and contribute to our growing understanding of the evolution and function of the gap gene network outside of Drosophila. [ABSTRACT FROM AUTHOR]

Abstract Background Hox transcription factors specify segmental diversity along the anterior-posterior body axis in metazoans. While the different Hox family members show clear functional specificity in vivo, they all show similar binding specificity in vitro and a satisfactory understanding of in vivo Hox target selectivity is still lacking. Results Using transient transfection in Kc167 cells, we systematically analyze the binding of all eight Drosophila Hox proteins. We find that Hox proteins show considerable binding selectivity in vivo even in the absence of canonical Hox cofactors Extradenticle and Homothorax. Hox binding selectivity is strongly associated with chromatin accessibility, being highest in less accessible chromatin. Individual Hox proteins exhibit different propensities to bind less accessible chromatin, and high binding selectivity is associated with high-affinity binding regions, leading to a model where Hox proteins derive binding selectivity through affinity-based competition with nucleosomes. Extradenticle/Homothorax cofactors generally facilitate Hox binding, promoting binding to regions in less accessible chromatin but with little effect on the overall selectivity of Hox targeting. These cofactors collaborate with Hox proteins in opening chromatin, in contrast to the pioneer factor, Glial cells missing, which facilitates Hox binding by independently generating accessible chromatin regions. Conclusions These studies indicate that chromatin accessibility plays a key role in Hox selectivity. We propose that relative chromatin accessibility provides a basis for subtle differences in binding specificity and affinity to generate significantly different sets of in vivo genomic targets for different Hox proteins.

Sexual dimorphism in digit ration is related to genetic differences between species in response to prenatal exposure to hormones. In this study, the development of tetrapod digits, preliminary the ratio between the length of digit II and IV (2D: 4D) was investigated in 34 samples of Darevskia cholorogaster in the North of Iran. The results showed no significant differences between sexes in any digit length. The digit ratio 2D: 4D was different between males and females in which the females had greater 2D: 4D in forelimb than the males. However, this difference was not significant. Sexual dimorphism in 2D: 4D, 3D: 4D and 2D: 3D ratios for the male and female showed no correlation within sex. Our results supported a genetic pattern seen in humans and most mammals, inconsistent with basic genetic pattern in reptiles. We concluded that the digits ratios observed in D. cholorogaster could be referred to microhabitat use by this species on different surfaces, besides basic genetic pattern and other ecological effects as foraging and mating.

Hepatitis C virus (HCV) infection causes liver pathologies, including hepatocellular carcinoma (HCC). Homeobox (HOX) gene products regulate embryonic development and are associated with tumorigenesis, although the regulation of HOX genes by HCV infection has not been clarified in detail. We examined the effect of HCV infection on HOX gene expression. In this study, HCV infection induced more than half of the HOX genes and reduced the level of histone H2A monoubiquitination on lysine 119 (K119) (H2Aub), which represses HOX gene promoter activity. HCV infection also promoted proteasome-dependent degradation of RNF2, which is an E3 ligase mediating H2A monoubiquitination as a component of polycomb repressive complex 1. Since full-genomic replicon cells but not subgenomic replicon cells exhibited reduced RNF2 and H2Aub levels and induction of HOX genes, we focused on the core protein. Expression of the core protein reduced the amounts of RNF2 and H2Aub and induced HOX genes. Treatment with LY-411575, which can reduce HCV core protein expression via signal peptide peptidase (SPP) inhibition without affecting other viral proteins, dose-dependently restored the amounts of RNF2 and H2Aub in HCV-infected cells and impaired the induction of HOX genes and production of viral particles but not viral replication. The chromatin immunoprecipitation assay results also indicated infection- and proteasome-dependent reductions in H2Aub located in HOX gene promoters. These results suggest that HCV infection or core protein induces HOX genes by impairing histone H2A monoubiquitination via a reduction in the RNF2 level. [ABSTRACT FROM AUTHOR]

The eyespot patterns found on the wings of nymphalid butterflies are novel traits that originated first in hindwings and subsequently in forewings, suggesting that eyespot development might be dependent on Hox genes. Hindwings differ from forewings in the expression of Ultrabithorax (Ubx), but the function of this Hox gene in eyespot development as well as that of another Hox gene Antennapedia (Antp), expressed specifically in eyespots centers on both wings, are still unclear. We used CRISPR-Cas9 to target both genes in Bicyclus anynana butterflies. We show that Antp is essential for eyespot development on the forewings and for the differentiation of white centers and larger eyespots on hindwings, whereas Ubx is essential not only for the development of at least some hindwing eyespots but also for repressing the size of other eyespots. Additionally, Antp is essential for the development of silver scales in male wings. In summary, Antp and Ubx, in addition to their conserved roles in modifying serially homologous segments along the anterior-posterior axis of insects, have acquired a novel role in promoting the development of a new set of serial homologs, the eyespot patterns, in both forewings (Antp) and hindwings (Antp and Ubx) of B. anynana butterflies. We propose that the peculiar pattern of eyespot origins on hindwings first, followed by forewings, could be due to an initial co-option of Ubx into eyespot development followed by a later, partially redundant, co-option of Antp into the same network. [ABSTRACT FROM AUTHOR]

Atherosclerosis, a dominant driving force underlying multiple cardiovascular events, is an intertwined and chronic inflammatory disease characterized by lipid deposition in the arterial wall, which leads to diverse cardiovascular problems. Despite unprecedented advances in understanding the pathogenesis of atherosclerosis and the substantial decline in cardiovascular mortality, atherosclerotic cardiovascular disease remains a global public health issue. Understanding the molecular landscape of atherosclerosis is imperative in the field of molecular cardiology. Recently, compelling evidence has shown that an important family of homeobox (HOX) genes endows causality in orchestrating the interplay between various cardiovascular biological processes and atherosclerosis. Despite seemingly scratching the surface, such insight into the realization of biology promises to yield extraordinary breakthroughs in ameliorating atherosclerosis. Primarily recapitulated herein are the contributions of HOX in atherosclerosis, including diverse cardiovascular biology, knowledge gaps, remaining challenges and future directions. A snapshot of other cardiovascular biological processes was also provided, including cardiac/vascular development, cardiomyocyte pyroptosis/apoptosis, cardiac fibroblast proliferation and cardiac hypertrophy, which are responsible for cardiovascular disorders. Further in‑depth investigation of HOX promises to provide a potential yet challenging landscape, albeit largely undetermined to date, for partially pinpointing the molecular mechanisms of atherosclerosis. A plethora of new targeted therapies may ultimately emerge against atherosclerosis, which is rapidly underway. However, translational undertakings are crucially important but increasingly challenging and remain an ongoing and monumental conundrum in the field.

Abstract Background The cytogenetic aberrations were considered as markers for diagnosis and prognosis in acute myeloid leukemia (AML), while the expression and regulation under different cytogenetic groups remain to be fully elucidated. Methods In this paper, for favorable, poor, and cytogenetically normal groups of AML patients, we performed comprehensive bioinformatics analyses including identifying differentially expressed genes (DEGs) and microRNAs (miRNAs) among them, functional enrichment and regulatory networks. Results We found that DEGs were enriched in membrane‐related processes. Eleven genes and two miRNAs were significantly differentially expressed among these three AML groups. In survival analysis, membrane‐related genes and several miRNAs were significant on prognostic outcome. Notably, six HOXA and three HOXB genes were significantly in low expression and high methylation in AML with favorable cytogenetics. Meanwhile, the miRNA‐HOX gene co‐regulatory networks revealed that HOXA5 was a hub node and regulated an AML oncogene SPARC. Conclusion Our work may provide novel insights to the molecular characteristics and classification between AML with different cytogenetics.

Relay of muscle-derived sensory information to the CNS is essential for the execution of motor behavior, but how proprioceptive sensory neurons (pSNs) establish functionally appropriate connections is poorly understood. A prevailing model of sensory-motor circuit assembly is that peripheral, target-derived, cues instruct pSN identities and patterns of intraspinal connectivity. To date no known intrinsic determinants of muscle-specific pSN fates have been described in vertebrates. We show that expression of Hox transcription factors defines pSN subtypes, and these profiles are established independently of limb muscle. The Hoxc8 gene is expressed by pSNs and motor neurons (MNs) targeting distal forelimb muscles, and sensory-specific depletion of Hoxc8 in mice disrupts sensory-motor synaptic matching, without affecting pSN survival or muscle targeting. These results indicate that the diversity and central specificity of pSNs and MNs are regulated by a common set of determinants, thus linking early rostrocaudal patterning to the assembly of limb control circuits.

Tribolium castaneum is a small and low maintenance beetle that has emerged as a most suitable insect model for studying developmental biology and functional genetic analysis. Diverse population genetic studies have been conducted using Tribolium as the principal model to establish basic facts and principles of inbreeding experiments and response to the selection and other quantitative genetics fundamentals. The advanced molecular genetic studies presently focused on the use of Tribolium as a typical invertebrate model for higher diploid eukaryotes. After a whole genome sequencing of Tribolium, many areas of functional genomics were unraveled, which enabled the use of it in many technical approaches of genomics. The present text reviews the use of Tribolium in techniques such as RNAi, transgenic studies, immune priming, immunohistochemistry, in situ hybridization, gene sequencing for characterization of microRNAs, and gene editing using engineered endonuclease. In contrast to Drosophila, the T. castaneum holds a robust systemic RNAi response, which makes it an excellent model for comparative functional genetic studies.

Background: The cytogenetic aberrations were considered as markers for diagnosis and prognosis in acute myeloid leukemia (AML), while the expression and regulation under different cytogenetic groups remain to be fully elucidated. Methods: In this paper, for favorable, poor, and cytogenetically normal groups of AML patients, we performed comprehensive bioinformatics analyses including identifying differentially expressed genes (DEGs) and microRNAs (miRNAs) among them, functional enrichment and regulatory networks. Results: We found that DEGs were enriched in membrane‐related processes. Eleven genes and two miRNAs were significantly differentially expressed among these three AML groups. In survival analysis, membrane‐related genes and several miRNAs were significant on prognostic outcome. Notably, six HOXA and three HOXB genes were significantly in low expression and high methylation in AML with favorable cytogenetics. Meanwhile, the miRNA‐HOX gene co‐regulatory networks revealed that HOXA5 was a hub node and regulated an AML oncogene SPARC. Conclusion: Our work may provide novel insights to the molecular characteristics and classification between AML with different cytogenetics. [ABSTRACT FROM AUTHOR]

During development, cell fate decisions are often highly stochastic, but with the frequency of the different possible fates tightly controlled. To understand how signaling networks control the cell fate frequency of such random decisions, we studied the stochastic decision of the Caenorhabditis elegans P3.p cell to either fuse to the hypodermis or assume vulva precursor cell fate. Using time-lapse microscopy to measure the single-cell dynamics of two key inhibitors of cell fusion, the Hox gene LIN-39 and Wnt signaling through the β-catenin BAR-1, we uncovered significant variability in the dynamics of LIN-39 and BAR-1 levels. Most strikingly, we observed that BAR-1 accumulated in a single, 1–4 ​h pulse at the time of the P3.p cell fate decision, with strong variability both in pulse slope and time of pulse onset. We found that the time of BAR-1 pulse onset was delayed relative to the time of cell fusion in mutants with low cell fusion frequency, linking BAR-1 pulse timing to cell fate outcome. Overall, a model emerged where animal-to-animal variability in LIN-39 levels and BAR-1 pulse dynamics biases cell fate by modulating their absolute level at the time cell fusion is induced. Our results highlight that timing of cell signaling dynamics, rather than its average level or amplitude, could play an instructive role in determining cell fate. Image 1 • The fate of the C. elegans P3.p cell is stochastic. • β-catenin (BAR-1) accumulated in P3.p at the time of the cell fate decision. • There is variability in dynamics of Hox and β-catenin levels during the decision. • BAR-1 accumulated with variable pulse slope and time of pulse onset. • Pulse dynamics bias cell fate at the time of the cell fate decision. [ABSTRACT FROM AUTHOR]

Background: Hox transcription factors are master regulators of animal development. Although highly conserved, they can contribute to the formation of novel biological characteristics when modified, such as during the generation of hybrid species, thus potentially serving as species-specific molecular markers. Here, we systematically studied the evolution of genomic sequences of Hox loci in an artificial allotetraploid lineage (4nAT, 4n = 200) derived from a red crucian carp (♀, RCC, 2n = 100) × common carp (♂, CC, 2n = 100) cross and its parents (RCC and CC). Results: PCR amplification yielded 23 distinct Hox gene fragments from 160 clones in 4nAT, 22 fragments from 90 clones in RCC, and 19 fragments from 90 clones in CC. Sequence alignment of the HoxA3a and HoxC10a genes indicated both the inheritance and loss of paternal genomic DNA in 4nAT. The HoxA5a gene from 4nAT consisted of two subtypes from RCC and two subtypes from CC, indicating that homologous recombination occurred in the 4nAT hybrid genome. Moreover, 4nAT carried genomic pseudogenization in the HoxA10b and HoxC13a loci. Interestingly, a new type of HoxC9a gene was found in 4nAT as a hybrid sequence of CC and RCC by recombination in the intronic region. Conclusion: The results revealed the influence of Hox genes during polyploidization in hybrid fish. The data provided insight into the evolution of vertebrate genomes and might be benefit for artificial breeding programs. [ABSTRACT FROM AUTHOR]

The Hox gene labial (lab) governs the formation of the tritocerebral head segment in insects and spiders. However, the morphology that results from lab action is very different in the two groups. In insects, the tritocerebral segment (intercalary segment) is reduced and lacks appendages, whereas in spiders the corresponding segment (pedipalpal segment) is a proper segment including a pair of appendages (pedipalps). It is likely that this difference between lab action in insects and spiders is mediated by regulatory targets or interacting partners of lab. However, only a few such genes are known in insects and none in spiders. We have conducted a candidate gene screen in the spider Parasteatoda tepidariorum using as candidates Drosophila melanogaster genes known to (potentially) interact with lab or to be expressed in the intercalary segment. We have studied 75 P. tepidariorum genes (including previously published and duplicated genes). Only 3 of these (proboscipedia-A (pb-A) and two paralogs of extradenticle (exd)) showed differential expression between leg and pedipalp. The low success rate points to a weakness of the candidate gene approach when it is applied to lineage specific organs. The spider pedipalp has no counterpart in insects, and therefore relying on insect data apparently cannot identify larger numbers of factors implicated in its specification and formation. We argue that in these cases a de novo approach to gene discovery might be superior to the candidate gene approach. [ABSTRACT FROM AUTHOR]

We aimed to discover cell line‐specific overexpressed HOX genes responsible for chemoresistance and to identify the mechanisms behind HOX‐induced cell line‐specific chemoresistance in EOC. Ten HOX genes and eight EOC cell lines were tested for any cell line‐specific overexpression that presents a mutually exclusive pattern. Cell viability was evaluated after treatment with cisplatin and/or siRNA for cell line‐specific overexpressed HOX genes. Immunohistochemical (IHC) staining for HOXB9 was performed in 84 human EOC tissues. HOXA10 and HOXB9 were identified as cell line‐specific overexpressed HOX genes for SKOV‐3 and RMUG‐S, respectively. Inhibiting the expression of cell line‐specific HOX genes, but not of other HOX genes, significantly decreased cell viability. In SKOV‐3 cells, cell viability decreased to 46.5% after initial 10 µM cisplatin treatment; however, there was no further decrease upon additional treatment with HOXA10 siRNA. In contrast, cell viability did not significantly decrease upon cisplatin treatment in RMUG‐S cells, but decreased to 65.5% after additional treatment with HOXB9 siRNA. In both cell lines, inhibiting cell line‐specific HOX expression enhanced apoptosis but suppressed the expression of epithelial‐mesenchymal transition (EMT) markers such as vimentin, MMP9, and Oct4. IHC analysis showed that platinum‐resistant cancer tissues more frequently had high HOXB9 expression than platinum‐sensitive cancer tissues. HOXB9, which is overexpressed in RMUG‐S but not in SKOV‐3 cells, appeared to be associated with cell line‐specific platinum resistance in RMUG‐S. Inhibiting HOXB9 overexpression in RMUG‐S cells may effectively eliminate platinum‐resistant ovarian cancer cells by facilitating apoptosis and inhibiting EMT. [ABSTRACT FROM AUTHOR]

Abstract Background Allotetraploid F1 hybrids (4nF1) (AABB, 4n = 148) were generated from the distant hybridization of Carassius auratus red var. (RCC) (AA, 2n = 100) (♀) × Megalobrama amblycephala (BSB) (BB, 2n = 48) (♂). It has been reported that Hox gene clusters are highly conserved among plants and vertebrates. In this study, we investigated the genomic organization of Hox gene clusters in the allotetraploid F1 hybrids and their parents to investigate the polyploidization process. Results There were three copies of Hox genes in the 4nF1 hybrids, two copies in RCC and one copy in BSB. In addition, obvious variation and pseudogenization were observed in some Hox genes from 4nF1. Conclusion Our results reveal the influence of polyploidization on the organization and evolution of Hox gene clusters in fish and also clarify some aspects of vertebrate genome evolution.

Homeobox (HOX) genes encode highly conserved transcription factors that play vital roles in embryonic development. DNA methylation is a pivotal regulatory epigenetic signaling mark responsible for regulating gene expression. Abnormal DNA methylation is largely associated with the aberrant expression of HOX genes, which is implicated in a broad range of human diseases, including cancer. Numerous studies have clarified the mechanisms of DNA methylation in both physiological and pathological processes. In this review, we focus on how DNA methylation regulates HOX genes and briefly discuss drug development approaches targeting these mechanisms. • DNA methylation is an important mechanism regulating the expression of HOX genes. • Histone methylation and lncRNAs are involved in DNA methylation of HOX genes. • DNA methylation level of HOX genes could be considered a biomarker for diagnostics. [ABSTRACT FROM AUTHOR]

• Hox genes in Mytilus coruscus at the genome level were used to speculated the formation of subcluster collinearity in gene structure, synteny and evolution analysis. • The Hox gene expression profile in larval stages suggests the existence of subcluster collinearity in M. coruscus. • The clustering of Hox sequences in M. coruscus was different with the clustering between species. • Hox genes in bivalves provided the basis for the expression patterns of four Hox subclusters. Hox genes encode transcription factors that are crucial regulators of various developmental processes, including patterning of the body axis and differentiation of cells, tissues and organs. They are organized in clusters in a wide range of Metazoans and expressed during embryonic development in a collinear manner from the 3′ to the 5′ end of these genomic units. Hox genes are part of the larger homeobox gene super-class, and other gene clusters beyond Hox are being increasingly discovered. This transcriptional dynamic generates spatiotemporal expression patterns throughout the developing body that are required for the establishment of fields of cell identity. Here we suggest that subcluster temporal collinearity may occur during the development of a bivalve species, as demonstrated for other Bilateran species. We performed a genome-wide analysis of the Mytilus coruscus Hox gene family, including gene structure, synteny, and expression patterns. It was shown that 11 Hox genes were evenly distributed within one chromosome in M. coruscus. Phylogenetic analysis showed that 11 Hox proteins were divided into four groups and each of them contained different conserved motifs. Besides, sequence alignment and analysis showed the conservation of 11 Hox genes of M. coruscus. Selection pressure analysis revealed the Ka/Ks ratios of Hox1 , Hox4 , Lox4 , Post2 , and Post1 were less than 1 in Bivalvia, indicating that these five Hox genes suffered significant purifying selection. Notably, Hox1 , Hox4 , Post2 were overlapped with the leading gene in the subcluster collinearity. This discovery suggests the potential existence of subcluster temporal collinearity in M. coruscus , which adds new insights into Hox gene organization in Bivalvia or Mollusca. [ABSTRACT FROM AUTHOR]

We have examined the expression of three paralogous Hox genes from E11.5 through E15.5 in the mouse spinal cord. These ages coincide with major phases of spinal cord neurogenesis, neuronal differentiation, cell migration, gliogenesis, and motor neuron cell death. The three genes, Hoxa10, Hoxc10, and Hoxd10, are all expressed in the lumbar spinal cord and have distinct expression patterns. Mutations in these three genes are known to affect motor neuron patterning. All three genes show lower levels of expression at the rostral limits of their domains, with selective regions of higher expression more caudally. Hoxa10 and Hoxd10 expression appears confined to post-mitotic cell populations in the intermediate and ventral gray, while Hoxc10 is also expressed in proliferating cells in the dorsal ventricular zone. Hoxc10 and Hoxd10 expression is clearly excluded from the lateral motor columns at rostral lumbar levels but is present in this region more caudally. Double labeling demonstrates that Hoxc10 expression is correlated with ventrolateral LIM gene expression in the caudal part of the lumbar spinal cord. (c) 2005 Elsevier B.V. All rights reserved.

Background: Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within isocitrate dehydrogenase (IDH)-mutant gliomas, there is a high variability in survival and a need to more accurately predict outcome., Methods: To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrative molecular analysis (using methylation, mRNA, copy number variation (CNV), and mutation data), analyzing a total of 729 IDH-mutant samples including a test set of 99 from University Health Network (UHN) and 2 validation cohorts including the German Cancer Research Center (DKFZ) and The Cancer Genome Atlas (TCGA)., Results: Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into 2 prognostic groups strongly predicting survival that were validated using 2 independent cohorts from TCGA and DKFZ (all P-values < .0001). The methylation signatures that predicted poor outcomes also exhibited high CNV instability and hypermethylation of HOX gene probes. Integrated multi-platform analyses using mRNA and methylation (iRM) showed that parallel HOX gene overexpression and simultaneous hypermethylation were significantly associated with increased mutational load, high aneuploidy, and worse survival (P-value < .0001). A 7-HOX gene signature was developed and validated using the most significantly associated HOX genes with patient outcome in both 1p/19q codeleted and non-codeleted IDHmut gliomas., Conclusions: HOX gene methylation and expression provide important prognostic information in IDH-mutant gliomas that are not captured by current molecular diagnostics. A 7-HOX gene signature of outcome shows significant survival differences in both 1p/19q codeleted and non-codeleted IDH-mutant gliomas., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In social insects, interactions among colony members trigger caste differentiation with morphological modifications. In termite soldier differentiation, the mandible size considerably increases through two moltings (via the presoldier stage) under the control of juvenile hormone (JH). Regulatory genes are predicted to provide patterning information that induces the mandible-specific cell proliferation. To identify factors responsible for the mandibular enlargement, expression analyses of 18 candidate genes were carried out in the termite Hodotermopsis sjostedti. Among those, dachshund (dac), which identifies the intermediate domain along the proximodistal appendage axis, showed mandible-specific upregulation prior to the molt into presoldiers, which can explain the pattern of cell proliferation for the mandibular elongation. Knockdown of dac by RNAi reduced the mandibular length and distorted its morphology. Furthermore, the epistatic relationships among Methoprene tolerant, Insulin receptor, Deformed (Dfd) and dac were revealed by combined RNAi and qRT-PCR analyses, suggesting that dac is regulated by Dfd, downstream of the JH and insulin signaling pathways. Thus, caste-specific morphogenesis is controlled by interactions between the factors that provide spatial information and physiological status. [ABSTRACT FROM AUTHOR]

The distal part of the tetrapod limb, the autopod, is characterized by the presence of digits. The digits display a wide diversity of shapes and number reflecting selection pressure for functional adaptation. Despite extensive study, the different aspects of digit patterning, as well as the factors and mechanisms involved are not completely understood. Here, we review the evidence implicating Hox proteins in digit patterning and the interaction between Hox genes and the Sonic hedgehog/Gli3 pathway, the other major regulator of digit number and identity. Currently, it is well accepted that a self-organizing Turing-type mechanism underlies digit patterning, this being understood as the establishment of an iterative arrangement of digit/interdigit in the hand plate. We also discuss the involvement of 5' Hox genes in regulating digit spacing in the digital plate and therefore the number of digits formed in this self-organizing system. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Since the discovery by Ed Lewis that the order of Hox genes on the chromosome reflects the partitioning of their patterning function along the anterior-posterior axis of the developing fruit fly embryo, extensive efforts have been dedicated to uncovering the regulatory events underlying the collinear expression of Hox genes. These studies have revealed various aspects of Hox regulation, including short-range and long-range transcriptional enhancers, insulator elements and non-coding RNAs. With the development of technologies allowing for high resolution probing of chromatin architecture, notably Chromosome Conformation Capture (3C)-based techniques, a clear relationship is emerging between long-range regulation of Hox genes and the three-dimensional organization of the genome. Here, we provide an overview of these studies and in particular we discuss the functional relevance of genome compartmentalization, CTCF- mediated insulation and the Polycomb Repressive Complexes in the remote control of Hox genes. [ABSTRACT FROM AUTHOR]

Precise regulation of Hox gene activity is essential to achieve proper control of animal embryonic development and to avoid generation of a variety of malignancies. This is a multilayered process, including complex polycistronic transcription, RNA processing, microRNA repression, long noncoding RNA regulation and sequence-specific translational control, acting together to achieve robust quantitative and qualitative Hox protein output. For many such mechanisms, the Hox cluster gene network has turned out to serve as a paradigmatic model for their study. In this review, we discuss current knowledge of how the different layers of post-transcriptional regulation and the production of a variety of noncoding RNA species control Hox output, and how this shapes formation of developmental systems that are reproducibly patterned by complex Hox networks. [ABSTRACT FROM AUTHOR]