Search Results (32)

Airway basal cells proliferate and regenerate airway epithelium after injury. The first step during airway epithelial repair is airway basal cell proliferation to close the wound. Previously, we demonstrated that homeobox (HOX) A1 expression is reduced in airway stem cells isolated from chronic obstructive pulmonary disease. HOXA1 is a developmental gene and plays a role in hematopoietic stem cell proliferation and differentiation, but its contribution to airway epithelial cell migration and proliferation is not known. In this study, we generated a HOXA1 knockout bronchial epithelial cell line using CRISPR/CAS9 technology followed by clonal expansion to investigate the role of HOXA1 in airway epithelial cell proliferation and migration. Compared to WT, HOXA1 knockout bronchial epithelial cells generated smaller spheroids than WT type cells, indicating a defect in cell proliferation. In the scratch assay, HOXA1 knockout cells showed substantial delay in migrating to the wounded area. By single-cell RNA sequencing and the clustering of cells based on HOXA1 expression, we identified a downregulation of genes involved in cell cycle progression. A cell cycle analysis by flow cytometry indicated partial cell cycle arrest at the G0/G1 phase in HOXA1 knockout cells. This was associated with a reduced expression of Cyclin E1 and an increased expression of the cyclin-dependent kinase inhibitor p21/CDKN1A. These results indicate that HOXA1 may contribute to cell proliferation by regulating cell cycle progression via p21/CDKN1A in airway epithelial cells. Full article

The HOX gene family encodes for regulatory transcription factors that play a crucial role in embryogenesis and differentiation of adult cells. This highly conserved family of genes consists of thirty-nine genes in humans that are located in four clusters, A–D, on different chromosomes. While early studies on the HOX gene family have been focused on embryonic development and its related disorders, research has shifted to examine aberrant expression of HOX genes and the subsequent implication in cancer prediction and progression. Due to their role of encoding master regulatory transcription factors, the abnormal expression of HOX genes has been shown to affect all stages of tumorigenesis and metastasis. This review highlights the novel role of the HOX family’s clinical relevance as both prognostic and diagnostic biomarkers in hematological and solid tumors. Full article

HOX genes play essential roles in patterning the anteroposterior axis of animal embryos and in the formation of various organs. In mammals, there are 39 HOX genes organized into four clusters (HOXA–D) located on different chromosomes. In relationship with their orderly arrangement along the chromosomes, these genes show nested expression patterns which imply that embryonic territories co-express multiple HOX genes along the main body axis. Interactomic database entries, as well as a handful of publications, support that some HOX proteins can form homodimers or interact with other HOX proteins. However, the consequences of HOX protein interactions have been poorly investigated and remain largely elusive. In this study, we compiled a repository of all HOX–HOX interactions from available databases, and taking HOXA1, HOXA2, and HOXA5 as examples, we investigated the capacity of HOX proteins to form homo- and heterodimers. We revealed that while the DNA-binding domain, the homeodomain, is not necessary for HOXA1 homodimerization, the nuclear localization of the dimerization is dependent on the homeodomain, particularly the integrity of the third helix of HOXA1. Furthermore, we demonstrated that HOXA1 can influence the localization of HOXA1 when it is deprived of the homeodomain, increasing its abundance in the chromatin-containing fraction. Moreover, HOXA1 nuclear homodimerization occurs independently of the integrity of the hexapeptide and, consequently, of its well-known interactor, the homeodomain protein PBX. These results hint at a potential involvement of dimerization in the complex landscape of HOX regulatory mechanisms. Full article

Fungal secondary metabolites (SMs) have broad applications in biomedicine, biocontrol, and the food industry. In this study, whole-genome sequencing and annotation of Taiwanofungus gaoligongensis were conducted, followed by comparative genomic analysis with 11 other species of Polyporales to examine genomic variations and secondary metabolite biosynthesis pathways. Additionally, transcriptome data were used to analyze the differential expression of polyketide synthase (PKS), terpene synthase (TPS) genes, and transcription factors (TFs) under different culture conditions. The results show that T. gaoligongensis differs from other fungal species in genome size (34.58 Mb) and GC content (50.72%). The antibiotics and Secondary Metabolites Analysis Shell (AntiSMASH) analysis reveals significant variation in the number of SM biosynthetic gene clusters (SMBGCs) across the 12 species (12–29), with T. gaoligongensis containing 25 SMBGCs: 4 PKS, 6 non-ribosomal peptide synthetase (NRPS), and 15 TPS clusters. The TgPKS1 gene is hypothesized to be involved in the biosynthesis of orsellinic acid or its derivatives, while TgPKS2 might catalyze the synthesis of 6-methylsalicylic acid (6MSA) and its derivatives. The TgTRI5 genes are suggested to synthesize tetracyclic sesquiterpene type B trichothecene compounds, while TgPentS may be involved in the synthesis of δ-cadinol, β-copaene, and α-murolene analogs or derivatives. Comparative genomic analysis shows that the genome size of T. gaoligongensis is similar to that of T. camphoratus, with comparable SMs. Both species share four types of PKS domains and five distinct types of TPS. Additionally, T. gaoligongensis exhibits a high degree of similarity to Laetiporus sulphureus, despite belonging to a different genus within the same family. Transcriptome analysis reveals significant variation in the expression levels of PKS and TPS genes across different cultivation conditions. The TgPKS1 and TgPKS4 genes, along with nine TgTFs, are significantly upregulated under three solid culture conditions. In contrast, under three different liquid culture conditions, the TgPKS3, TgTRI5-1, and TgTRI5-2 genes, along with twelve TgTFs, exhibit higher activity. Co-expression network analysis and TgTFs binding site prediction in the promoter regions of TgPKS and TgTPS genes suggest that TgMYB9 and TgFTD4 regulate TgPKS4 expression. TgHOX1, TgHSF2, TgHSF3, and TgZnF4 likely modulate TgPKS3 transcriptional activity. TgTRI5-1 and TgTRI5-5 expression is likely regulated by TgbZIP2 and TgZnF15, respectively. This study provides new insights into the regulatory mechanisms of SMs in T. gaoligongensis and offers potential strategies for enhancing the biosynthesis of target compounds through artificial intervention. Full article

Background/Objectives: Homeobox (HOX) genes encode conserved transcription factors essential for tissue and organ development and cellular differentiation. In humans, these genes are organized into four clusters: HOXA, HOXB, HOXC, and HOXD. While HOX genes have been extensively studied in cancer biology, their roles in esophageal squamous cell carcinoma (ESCC) remain poorly understood. Given the increasing incidence and high mortality rate of ESCC, exploring the molecular drivers of this tumor is urgent. Methods: Therefore, this study investigated the mutational landscape and expression profiles of HOX genes in ESCC and their differentially expressed targets using ESCC data from The Cancer Genome Atlas (TCGA) and two independent transcriptome datasets. Results: We found that copy number alterations and single nucleotide variations were rare, while seven HOX genes (HOXA2, HOXA7, HOXB13, HOXC9, HOXC10, HOXC13, and HOXD10) were significantly differentially expressed in ESCC compared to paired non-malignant mucosa. Further analysis identified 776 potential HOX target genes differentially expressed in ESCC, many of which are involved in critical cancer pathways such as PI3K-AKT, cell cycle regulation, and epithelial–mesenchymal transition (EMT). The HOXA7 overexpression was associated with poor overall survival rates in ESCC. This finding opens new possibilities for targeted therapies, offering hope for improved patient outcomes. Conclusions: Thus, this study underscored the pivotal role of HOX gene dysregulation in ESCC and classified HOXA7 as a potential prognostic biomarker in this tumor. Full article

Hox gene clusters are crucial in embryogenesis. It was observed that some Hox genes are located in order along the telomeric to centromeric direction of the DNA sequence: Hox1, Hox2, Hox3…. These genes are expressed in the same order in the ontogenetic units of the Drosophila embryo along the anterior–posterior axis. The two entities (genome and embryo) differ significantly in linear size and in-between distance. This strange phenomenon was named spatial collinearity (SP). Later, it was observed that, particularly in the vertebrates, a temporal collinearity (TC) coexists: first Hox1 is expressed, later Hox2, and later on Hox3…. According to a biophysical model (BM), pulling forces act at the anterior end of the cluster while a cluster fastening applies at the posterior end. Hox clusters are irreversibly elongated along the force direction. During evolution, the elongated Hox clusters are broken at variable lengths, thus split clusters may be created. An empirical rule was formulated, distinguishing development due to a complete Hox cluster from development due to split Hox clusters. BM can explain this empirical rule. In a spontaneous mutation, where the cluster fastening is dismantled, a weak pulling force automatically shifts the cluster inside the Hox activation domain. This cluster translocation can probably explain the absence of temporal collinearity in Drosophila. Full article

Parkinson’s disease (PD) is the most serious movement disorder, but the actual cause of this disease is still unknown. Induced pluripotent stem cell-derived neural cultures from PD patients carry the potential for experimental modeling of underlying molecular events. We analyzed the RNA-seq data of iPSC-derived neural precursor cells (NPCs) and terminally differentiated neurons (TDNs) from healthy donors (HD) and PD patients with mutations in PARK2 published previously. The high level of transcription of HOX family protein-coding genes and lncRNA transcribed from the HOX clusters was revealed in the neural cultures from PD patients, while in HD NPCs and TDNs, the majority of these genes were not expressed or slightly transcribed. The results of this analysis were generally confirmed by qPCR. The HOX paralogs in the 3′ clusters were activated more strongly than the genes of the 5′ cluster. The abnormal activation of the HOX gene program upon neuronal differentiation in the cells of PD patients raises the possibility that the abnormal expression of these key regulators of neuronal development impacts PD pathology. Further research is needed to investigate this hypothesis. Full article

Craniofacial tissues comprise highly evolved organs characterized by a relative lack of expression in the HOX family transcription factors. In the present study, we sought to define the epigenetic events that limit HOX gene expression from undifferentiated neural crest cells to semi-differentiated odontogenic progenitors and to explore the effects of elevated levels of HOX. The ChIP-chip data demonstrated high levels of repressive H3K27me3 marks on the HOX gene promoters in ES and cranial neural crest cells when compared to the H3K4me3 marks, while the K4/K27 ratio was less repressive in the odontogenic progenitors, dental follicle, dental pulp, periodontal ligament fibroblasts, alveolar bone osteoblasts, and cementoblasts. The gene expression of multiple HOX genes, especially those from the HOXA and HOXB clusters, was significantly elevated and many times higher in alveolar bone cells than in the dental follicle cells. In addition, the HOX levels in the skeletal osteoblasts were many times higher in the trunk osteoblasts compared to the alveolar bone osteoblasts, and the repressive mark H3K27me3 promoter occupancy was substantially and significantly elevated in the alveolar bone osteoblasts when compared to the trunk osteoblasts. To explore the effect of elevated HOX levels in craniofacial neural crest cells, HOX expression was induced by transfecting cells with the Cdx4 transcription factor, resulting in a significant decrease in the mineralization markers, RUNX2, OSX, and OCN upon HOX elevation. Promoting HOX gene expression in developing teeth using the small molecule EZH2 inhibitor GSK126 resulted in an increased number of patterning events, supernumerary cusp formation, and increased Hoxa4 and Hoxb6 gene expression when compared to the controls. Together, these studies illustrate the profound effects of epigenetic regulatory events at all stages of the differentiation of craniofacial peripheral tissues from the neural crest, including lineage specification, tissue differentiation, and patterning. Full article

The Senegalese sole (Solea senegalensis, Kaup 1858), a marine flatfish, belongs to the Pleuronectiformes order. It is a commercially important species for fisheries and aquaculture. However, in aquaculture, several production bottlenecks have still to be resolved, including skeletal deformities and high mortality during the larval and juvenile phase. The study aims to characterize the hox gene clusters in S. senegalensis to understand better the developmental and metamorphosis process in this species. Using a BAC library, the clones that contain hox genes were isolated, sequenced by NGS and used as BAC-FISH probes. Subsequently the hox clusters were studied by sequence analysis, comparative genomics, and cytogenetic and phylogenetic analysis. Cytogenetic analysis demonstrated the localization of four BAC clones on chromosome pairs 4, 12, 13, and 16 of the Senegalese sole cytogenomic map. Comparative and phylogenetic analysis showed a highly conserved organization in each cluster and different phylogenetic clustering in each hox cluster. Analysis of structural and repetitive sequences revealed accumulations of polymorphisms mediated by repetitive elements in the hoxba cluster, mainly retroelements. Therefore, a possible loss of the hoxb7a gene can be established in the Pleuronectiformes lineage. This work allows the organization and regulation of hox clusters to be understood, and is a good base for further studies of expression patterns. Full article

NUP98::NSD1 fusion, a cryptic translocation of t(5;11)(q35;p15.5), occurs predominantly in pediatric AML, having a poor prognostic outcome. There are limited studies on the diagnosis of NUP98::NSD1 fusion in a clinical setting, and most of the data are from Western countries. No study on the detection of this translocation has been reported from the Indian subcontinent to date. One possible reason could be the lack of availability of a potential tool to detect the fusion transcript. We have developed a real-time quantitative PCR (qRT-PCR)-based assay to detect NUP98::NSD1 fusion transcript with high sensitivity and specificity. Screening 150 AML patients (38 pediatric and 112 adults) using the assay showed the presence of fusion transcript in six patients including 03 pediatric, and 03 adult patients. We observed a prevalence rate of 7.89% (3/38) and 2.67% (3/112) fusion transcript in pediatric and adult patients, respectively. Sanger sequencing further validated the occurrence of NUP98::NSD1 fusion in all six patients. Molecular characterization of these patients revealed a co-occurrence of FLT3-ITD mutation, accompanied by altered expression of the HOX and other genes associated with AML. All six patients responded poorly to induction therapy. Overall, this is the first study to show the presence of the NUP98::NSD1 fusion transcript in Indian AML patients. Further, we demonstrate that our in-house developed qRT-PCR assay can be used to screen NUP98::NSD1 fusion in clinical settings. Full article

The Hox gene cluster, responsible for patterning of the head–tail axis, is an ancestral feature of all bilaterally symmetrical animals (the Bilateria) that remains intact in a wide range of species. We can say that the Hox cluster evolved successfully only once since it is commonly the same in all groups, with labial-like genes at one end of the cluster expressed in the anterior embryo, and Abd-B-like genes at the other end of the cluster expressed posteriorly. This review attempts to make sense of the Hox gene cluster and to address the following questions. How did the Hox cluster form in the protostome-deuterostome last common ancestor, and why was this with a particular head–tail polarity? Why is gene clustering usually maintained? Why is there collinearity between the order of genes along the cluster and the positions of their expressions along the embryo? Why do the Hox gene expression domains overlap along the embryo? Why have vertebrates duplicated the Hox cluster? Why do Hox gene knockouts typically result in anterior homeotic transformations? How do animals adapt their Hox clusters to evolve new structural patterns along the head–tail axis? Full article

Long non-coding RNAs (lncRNAs) play critical roles in human cancers. HOXA11 anti-sense RNA (HOXA11-AS) is an lncRNA belonging to the homeobox (HOX) gene cluster that promotes liver metastasis in human colon cancer. However, its role and mechanism of action in human oral squamous cell carcinoma (OSCC) are unclear. In this study, we investigated HOXA11-AS expression and function in human OSCC tissues and cell lines, as well as a mouse model of OSCC. Our analyses showed that HOXA11-AS expression in human OSCC cases correlates with lymph node metastasis, nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase 1 (NQO1) upregulation, and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) downregulation. Using the human OSCC cell lines HSC3 and HSC4, we demonstrate that HOXA11-AS promotes NQO1 expression by sponging microRNA-494. In contrast, HOXA11-AS recruits zeste homolog 2 (EZH2) to the NQO2 promoter to suppress its expression via the trimethylation of H3K27. The upregulation of NQO1 enzymatic activity by HOXA11-AS results in the consumption of flavin adenine dinucleotide (FAD), which reduces FAD-requiring glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity and suppresses glycolysis. However, our analyses show that lactic acid fermentation levels are preserved by glutaminolysis due to increased malic enzyme-1 expression, promoting enhanced proliferation, invasion, survival, and drug resistance. In contrast, suppression of NQO2 expression reduces the consumption of NRH via NQO2 enzymatic activity and increases NAD levels, which promotes enhanced stemness and metastatic potential. In mouse tumor models, knockdown of HOXA11-AS markedly suppressed tumor growth and lung metastasis. From these findings, targeting HOXA11-AS may strongly suppress high-grade OSCC by regulating both NQO1 and NQO2. Full article

Hox genes play a crucial role in morphogenesis, especially in anterior–posterior body axis patterning. The organization of Hox clusters in vertebrates is a result of several genome duplications: two rounds of duplication in the ancestors of all vertebrates and a third round that was specific for teleost fishes. Teleostei cluster structure has been significantly modified in the evolutionary processes by Hox gene losses and co-options, while mammals show no such tendency. In mammals, the Hox gene number in a single cluster is stable and generally large, and the numbers are similar to those in the Chondrichthyes. Hox gene alternative splicing activity slightly differs between fishes and mammals. Fishes and mammals have differences in their known alternative splicing activity for Hox gene distribution along the anterior–posterior body axis. The analyzed fish groups—the Coelacanthiformes, Chondrichthyes, and Teleostei—all have higher known alternative mRNA numbers from the anterior and posterior regions, whereas mammals have a more uniform Hox transcript distribution along this axis. In fishes, most Hox transcripts produce functioning proteins, whereas mammals have significantly more known transcripts that do not produce functioning proteins. Full article

The extant reptiles are one of the most diverse clades among terrestrial vertebrates and one of a few groups with instances of parthenogenesis. Due to the hybrid origin of parthenogenetic species, reference genomes of the parental species as well as of the parthenogenetic progeny are indispensable to explore the genetic foundations of parthenogenetic reproduction. Here, we report on the first genome assembly of rock lizard Darevskia valentini, a paternal species for several parthenogenetic lineages. The novel genome was used in the reconstruction of the comprehensive phylogeny of Squamata inferred independently from 7369 trees of single-copy orthologs and a supermatrix of 378 conserved proteins. We also investigated Hox clusters, the loci that are often regarded as playing an important role in the speciation of animal groups with drastically diverse morphology. We demonstrated that Hox clusters of D. valentini are invaded with transposons and contain the HoxC1 gene that has been considered to be lost in the amniote ancestor. This study provides confirmation for previous works and releases new genomic data that will contribute to future discoveries on the mechanisms of parthenogenesis as well as support comparative studies among reptiles. Full article

Angiosarcoma is a rare, devastating malignancy with few curative options for disseminated disease. We analyzed a recently published genomic data set of 48 angiosarcomas and noticed recurrent amplifications of HOXA-cluster genes in 33% of patients. HOXA genes are master regulators of embryonic vascular development and adult neovascularization, which provides a molecular rationale to suspect that amplified HOXA genes act as oncogenes in angiosarcoma. HOXA amplifications typically affected multiple pro-angiogenic HOXA genes and co-occurred with amplifications of CD36 and KDR, whereas the overall mutation rate in these tumors was relatively low. HOXA amplifications were found most commonly in angiosarcomas located in the breast and were rare in angiosarcomas arising in sun-exposed areas on the head, neck, face and scalp. Our data suggest that HOXA-amplified angiosarcoma is a distinct molecular subgroup. Efforts to develop therapies targeting oncogenic HOX gene expression in AML and other sarcomas may have relevance for HOXA-amplified angiosarcoma. Full article