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1.
Tumour Biol ; 43(1): 263-278, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34633333

RESUMO

BACKGROUND: Expression dysregulation of HOX homeobox genes has been observed in several cancers, including head and neck squamous cell carcinoma (HNSC). Although characterization of HOX gene roles in HNSC development has been reported, there is still a need to better understand their real contribution to tumorigenesis. OBJECTIVE: The present study aimed to evaluate the contribution of the protein-coding HOX genes (HOXA10, HOXC9, HOXC10, and HOXC13) in cellular processes related to carcinogenesis and progression of the HNSC. METHODS: Expression of HOX genes was analyzed in HNSC RNA-Seq data from The Cancer Genome Atlas (TCGA) and by RT-qPCR in different tumor cell lines. siRNA-mediated knockdown of HOXA10, HOXC9, HOXC10 or HOXC13 was performed in HNSC cell lines, and predicted transcriptional targets HOX genes was analyzed by bioinformatic. RESULTS: Thirty-one out of the 39 mammalian HOX genes were found upregulated in HNSC tissues and cell lines. The HOXC9, HOXC10 or HOXC13 knockdown attenuated cell migration, and lead to downregulation of epithelial-mesenchymal transition (EMT) markers, which were predicted as transcriptional targets of these three HOX genes. Diminished colony formation and cell cycle arrest after HOXC10 or HOXC13 knockdown were also observed, corroborating the fact that there was an enrichment for genes in proliferation/cell cycle pathways. CONCLUSIONS: In summary, we revealed roles for HOXC9, HOXC10, and HOXC13 in cell migration and proliferation/cell cycle progression in HNSC cells and suggested that those HOX members contribute to HNSC development possibly by regulating tumor growth and metastasis.


Assuntos
Genes Homeobox/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Biomarcadores Tumorais/genética , Carcinogênese/genética , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Regulação para Cima
3.
Chin Med J (Engl) ; 134(19): 2340-2352, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34561318

RESUMO

BACKGROUND: Emerging evidence indicates that the sineoculis homeobox homolog 1-eyes absent homolog 1 (SIX1-EYA1) transcriptional complex significantly contributes to the pathogenesis of multiple cancers by mediating the expression of genes involved in different biological processes, such as cell-cycle progression and metastasis. However, the roles of the SIX1-EYA1 transcriptional complex and its targets in colorectal cancer (CRC) are still being investigated. This study aimed to investigate the roles of SIX1-EYA1 in the pathogenesis of CRC, to screen inhibitors disrupting the SIX1-EYA1 interaction and to evaluate the efficiency of small molecules in the inhibition of CRC cell growth. METHODS: Real-time quantitative polymerase chain reaction and western blotting were performed to examine gene and protein levels in CRC cells and clinical tissues (collected from CRC patients who underwent surgery in the Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, between 2016 and 2018, n = 24). In vivo immunoprecipitation and in vitro pulldown assays were carried out to determine SIX1-EYA1 interaction. Cell proliferation, cell survival, and cell invasion were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, clonogenic assay, and Boyden chamber assay, respectively. The Amplified Luminescent Proximity Homogeneous Assay Screen (AlphaScreen) method was used to obtain small molecules that specifically disrupted SIX1-EYA1 interaction. CRC cells harboring different levels of SIX1/EYA1 were injected into nude mice to establish tumor xenografts, and small molecules were also injected into mice to evaluate their efficiency to inhibit tumor growth. RESULTS: Both SIX1 and EYA1 were overexpressed in CRC cancerous tissues (for SIX1, 7.47 ±â€Š3.54 vs.1.88 ±â€Š0.35, t = 4.92, P = 0.008; for EYA1, 7.61 ±â€Š2.03 vs. 2.22 ±â€Š0.45, t = 6.73, P = 0.005). The SIX1/EYA1 complex could mediate the expression of two important genes including cyclin A1 (CCNA1) and transforming growth factor beta 1 (TGFB1) by binding to the myocyte enhancer factor 3 consensus. Knockdown of both SIX1 and EYA1 could decrease cell proliferation, cell invasion, tumor growth, and in vivo tumor growth (all P < 0.01). Two small molecules, NSC0191 and NSC0933, were obtained using AlphaScreen and they could significantly inhibit the SIX1-EYA1 interaction with a half-maximal inhibitory concentration (IC50) of 12.60 ±â€Š1.15 µmol/L and 83.43 ±â€Š7.24 µmol/L, respectively. Administration of these two compounds could significantly repress the expression of CCNA1 and TGFB1 and inhibit the growth of CRC cells in vitro and in vivo. CONCLUSIONS: Overexpression of the SIX1/EYA1 complex transactivated the expression of CCNA1 and TGFB1, causing the pathogenesis of CRC. Pharmacological inhibition of the SIX1-EYA1 interaction with NSC0191 and NSC0933 significantly inhibited CRC cell growth by affecting cell-cycle progression and metastasis.


Assuntos
Neoplasias Colorretais , Proteínas de Homeodomínio , Animais , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Genes Homeobox , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Nus , Proteínas Nucleares/genética , Proteínas Tirosina Fosfatases/genética
4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1085-1092, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362486

RESUMO

OBJECTIVE: To investigate the effect and molecular mechanism of miR-142-3p to the proliferation, cycle and apoptosis of acute B lymphocytic leukemia (B-ALL) cells by regulating the homeobox gene 5 (HOXA5) expression. METHODS: Real-time fluorescence quantitative PCR was used to detect the expression levels of miR-142-3p and HOXA5 in human B-ALL cell Nalm6 cell line and human B lymphoblast Hmy2-cir cells. Nalm6 was transfected by using liposome transfection technology, miR-142-3p mimic, pcDNA-HOXA5 overexpression plasmid, miR-142-3p mimic+pcDNA-HOXA5 overexpression plasmid, and control. The binding site of HOXA5 and miR-142-3p was predicted according to microRNA.org, and the targeting relationship between miR-142-3p and HOXA5 gene was detected by double luciferase reporter gene experiment. The effect of miR-142-3p to the proliferation of Nalm6 cells was detected using the Cell Counting Box-8 (CCK-8) method and cell clone formation experiments. Flow cytometry was used to detect the effects of miR-142-3p to cell cycle distribution and apoptosis of Nalm6 cells. The expression levels of cell cycle-related proteins, including G1 /S-specific cyclin-D1 (CyclinD1), Cyclin-dependent kinase 4 (CDK4) and B-cell lymphoma/ leukemia-2 protein (BCL-2), BCL-2 related X protein (Bax), cysteine-aspartate-specific protease (Caspase-3) were detected by Western blot. RESULTS: Compared with Hmy2-cir cells, miR-142-3p showed low expression in Nalm6 cells and HOXA5 showed high expression (P<0.05). MiR-142-3p and HOXA5 3'-UTR showed complementary binding regions, the luciferase activity of miR-142-3p mimic and wild-type HOXA5 3'-UTR was significantly lower than that of miR-142-3p negative control and wild-type HOXA5 3'-UTR (P<0.05). The proliferation of Nalm6 cells and the number of cell clones could be inhibited by miR-142-3p mimic after 48 and 72 hours of transfection (P<0.05), which causing G1 phase arrest of Nalm6 cells and inhibiting the expression of CyclinD1 and CDK4 protein (P<0.01), promoting the apoptosis of Nalm6 cells, and inhibiting the expression of BCL-2 protein, moreover, promoting the expression of Bax and Caspase-3 protein (P<0.05). CONCLUSION: MiR-142-3p can inhibit the proliferation of Nalm6 cells by targeting down-regulation the expression of HOXA5, arrest the G1 phase of cells, and promote apoptosis of the cells.


Assuntos
Leucemia de Células B , MicroRNAs , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Genes Homeobox , Proteínas de Homeodomínio/genética , Humanos , Leucemia de Células B/genética , MicroRNAs/genética
5.
Proc Biol Sci ; 288(1956): 20211168, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34344178

RESUMO

Chelicerate arthropods exhibit dynamic genome evolution, with ancient whole-genome duplication (WGD) events affecting several orders. Yet, genomes remain unavailable for a number of poorly studied orders, such as Opiliones (daddy-long-legs), which has hindered comparative study. We assembled the first harvestman draft genome for the species Phalangium opilio, which bears elongate, prehensile appendages, made possible by numerous distal articles called tarsomeres. Here, we show that the genome of P. opilio exhibits a single Hox cluster and no evidence of WGD. To investigate the developmental genetic basis for the quintessential trait of this group-the elongate legs-we interrogated the function of the Hox genes Deformed (Dfd) and Sex combs reduced (Scr), and a homologue of Epidermal growth factor receptor (Egfr). Knockdown of Dfd incurred homeotic transformation of two pairs of legs into pedipalps, with dramatic shortening of leg segments in the longest leg pair, whereas homeosis in L3 is only achieved upon double Dfd + Scr knockdown. Knockdown of Egfr incurred shortened appendages and the loss of tarsomeres. The similarity of Egfr loss-of-function phenotypic spectra in insects and this arachnid suggest that repeated cooption of EGFR signalling underlies the independent gains of supernumerary tarsomeres across the arthropod tree of life.


Assuntos
Aracnídeos , Animais , Aracnídeos/genética , Extremidades , Genes Homeobox , Genoma , Insetos
6.
Elife ; 102021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34388088

RESUMO

Neuronal cell fate determinants establish the identities of neurons by controlling gene expression to regulate neuronal morphology and synaptic connectivity. However, it is not understood if neuronal cell fate determinants have postmitotic functions in synapse pattern formation. Here we identify a novel role for UNC-4 homeobox protein and its corepressor UNC-37/Groucho, in tiled synaptic patterning of the cholinergic motor neurons in Caenorhabditis elegans. We show that unc-4 is not required during neurogenesis but is required in the postmitotic neurons for proper synapse patterning. In contrast, unc-37 is required in both developing and postmitotic neurons. The synaptic tiling defects of unc-4 mutants are suppressed by bar-1/ß-catenin mutation, which positively regulates the expression of ceh-12/HB9. Ectopic ceh-12 expression partly underlies the synaptic tiling defects of unc-4 and unc-37 mutants. Our results reveal a novel postmitotic role of neuronal cell fate determinants in synapse pattern formation through inhibiting the canonical Wnt signaling pathway.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Expressão Gênica , Genes Homeobox , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas Correpressoras/genética , Proteínas de Homeodomínio/metabolismo , Mitose , Neurônios/fisiologia , Sinapses/fisiologia , Fatores de Transcrição/metabolismo
7.
Nat Rev Neurosci ; 22(10): 627-636, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34446866

RESUMO

The enormous diversity of cell types that characterizes any animal nervous system is defined by neuron-type-specific gene batteries that endow cells with distinct anatomical and functional properties. To understand how such cellular diversity is genetically specified, one needs to understand the gene regulatory programmes that control the expression of cell-type-specific gene batteries. The small nervous system of the nematode Caenorhabditis elegans has been comprehensively mapped at the cellular and molecular levels, which has enabled extensive, nervous system-wide explorations into whether there are common underlying mechanisms that specify neuronal cell-type diversity. One principle that emerged from these studies is that transcription factors termed 'terminal selectors' coordinate the expression of individual members of neuron-type-specific gene batteries, thereby assigning unique identities to individual neuron types. Systematic mutant analyses and recent nervous system-wide expression analyses have revealed that one transcription factor family, the homeobox gene family, is broadly used throughout the entire C. elegans nervous system to specify neuronal identity as terminal selectors. I propose that the preponderance of homeobox genes in neuronal identity control is a reflection of an evolutionary trajectory in which an ancestral neuron type was specified by one or more ancestral homeobox genes, and that this functional linkage then duplicated and diversified to generate distinct cell types in an evolving nervous system.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Genes Homeobox/fisiologia , Neurônios/fisiologia , Animais , Caenorhabditis elegans , Diferenciação Celular/fisiologia , Humanos
8.
Stem Cell Res Ther ; 12(1): 481, 2021 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454577

RESUMO

INTRODUCTION: Adipose tissue (AT) has become a source of mesenchymal stromal/stem cells (MSC) for regenerative medicine applications, in particular skeletal disorders. Several enzymatic or mechanical procedures have been proposed to process AT with the aim to isolate cells that can be locally implanted. How AT is processed may impact its properties. Thus, we compared AT processed by centrifugation (C-AT) to microfragmentation (MF-AT). Focusing on MF-AT, we subsequently assessed the impact of synovial fluid (SF) alone on both MF-AT and isolated AT-MSC to better understand their cartilage repair mechanisms. MATERIALS AND METHODS: MF-AT and C-AT from the same donors were compared by histology and qRT-PCR immediately after isolation or as ex vivo cultures using a micro-tissue pellet system. The in vitro impact of SF on MF-AT and AT-MSC was assessed by histological staining and molecular analysis. RESULTS: The main AT histological features (i.e., increased extracellular matrix and cellularity) of the freshly isolated or ex vivo-cultured MF-AT persisted compared to C-AT, which rapidly deteriorated during culture. Based on our previous studies of HOX genes in MSC, we investigated the involvement of Homeobox Protein HOX-B7 (HOXB7) and its target basic Fibroblast Growth Factor (bFGF) in the molecular mechanism underlying the improved performance of MF-AT. Indeed, both these biomarkers were more prominent in freshly isolated MF-AT compared to C-AT. SF alone preserved the AT histological features of MF-AT, together with HOXB7 and bFGF expression. Increased cell performance was also observed in isolated AT-MSC after SF treatment concomitant with enhanced HOXB7 expression, although there was no apparent association with bFGF. CONCLUSIONS: Our findings show that MF has a positive effect on the maintenance of AT histology and may trigger the expression of trophic factors that improve tissue repair by processed AT.


Assuntos
Genes Homeobox , Células-Tronco Mesenquimais , Tecido Adiposo , Diferenciação Celular , Células Cultivadas , Líquido Sinovial
9.
Development ; 148(16)2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34351412

RESUMO

The neuroblast timer genes hunchback, Krüppel, 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 Krüppel 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-Krüppel, 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.


Assuntos
Padronização Corporal/genética , Genes Homeobox , Proteínas de Homeodomínio/genética , Proteínas de Insetos/genética , Células-Tronco Neurais/metabolismo , Fatores do Domínio POU/genética , Tribolium/embriologia , Tribolium/genética , Animais , Blastoderma/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Desenvolvimento Embrionário/genética , Feminino , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Proteínas de Homeodomínio/metabolismo , Proteínas de Insetos/metabolismo , Masculino , Fatores do Domínio POU/metabolismo , Interferência de RNA , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
10.
Development ; 148(16)2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34387307

RESUMO

During early embryogenesis in amniotic vertebrates, the gonads differentiate into either ovaries or testes. The first cell lineage to differentiate gives rise to the supporting cells: Sertoli cells in males and pre-granulosa cells in females. These key cell types direct the differentiation of the other cell types in the gonad, including steroidogenic cells. The gonadal surface epithelium and the interstitial cell populations are less well studied, and little is known about their sexual differentiation programs. Here, we show the requirement of the homeobox transcription factor gene TGIF1 for ovarian development in the chicken embryo. TGIF1 is expressed in the two principal ovarian somatic cell populations: the cortex and the pre-granulosa cells of the medulla. TGIF1 expression is associated with an ovarian phenotype in estrogen-mediated sex reversal experiments. Targeted misexpression and gene knockdown indicate that TGIF1 is required, but not sufficient, for proper ovarian cortex formation. In addition, TGIF1 is identified as the first known regulator of juxtacortical medulla development. These findings provide new insights into chicken ovarian differentiation and development, specifically cortical and juxtacortical medulla formation.


Assuntos
Galinhas/genética , Genes Homeobox , Proteínas de Homeodomínio/genética , Ovário/embriologia , Proteínas Repressoras/genética , Animais , Diferenciação Celular , Linhagem da Célula/genética , Embrião de Galinha , Embrião de Mamíferos/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Gônadas/metabolismo , Proteínas de Homeodomínio/metabolismo , Masculino , Ovário/citologia , Ovário/metabolismo , Proteínas Repressoras/metabolismo , Células de Sertoli/metabolismo , Processos de Determinação Sexual/genética , Diferenciação Sexual/genética , Testículo/metabolismo
11.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208964

RESUMO

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are rare diseases occurring in the gastrointestinal tract and pancreas. They are characterized by the loss of epithelial tubular gland elements, and by the increased expression of neuroendocrine markers. GEP-NENs are subdivided into two histo-pathological types, gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs). According to WHO 2017 and 2019 classification criteria are graded and staged in four categories, NET-G1, NET-G2, NET-G3, and NEC-G3. The molecular characterization of these tumors can be fundamental for the identification of new diagnostic, prognostic and predictive biomarkers. The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes, normally involved in embryogenic development and frequently deregulated in human cancers, and of the HOX regulating lncRNA HOTAIR in GEP-NENs. The expression of HOX genes is gradually lost in the transition from GEP NET G1 to NET/NEC G3 tumors, while HOTAIR expression, inversely correlated with HOX genes expression and weakly expressed in low-grade GEP NENs, becomes aberrant in NET G3 and NEC G3 categories. Our data highlights their potential role in the molecular stratification of GEP-NENs by suggesting new prognostic markers and potential therapeutic targets.


Assuntos
Genes Homeobox , Neoplasias Intestinais/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , RNA Longo não Codificante/genética , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Intestinais/genética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Neoplasias Gástricas/genética , Regulação para Cima
12.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299303

RESUMO

Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. Several major mechanisms cause AF in patients, including genetic predispositions to AF development. Genome-wide association studies have identified a number of genetic variants in association with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription PITX2. Because of the inherent complexity of the human heart, experimental and basic research is insufficient for understanding the functional impacts of PITX2 variants on AF. Linking PITX2 properties to ion channels, cells, tissues, atriums and the whole heart, computational models provide a supplementary tool for achieving a quantitative understanding of the functional role of PITX2 in remodelling atrial structure and function to predispose to AF. It is hoped that computational approaches incorporating all we know about PITX2-related structural and electrical remodelling would provide better understanding into its proarrhythmic effects leading to development of improved anti-AF therapies. In the present review, we discuss advances in atrial modelling and focus on the mechanistic links between PITX2 and AF. Challenges in applying models for improving patient health are described, as well as a summary of future perspectives.


Assuntos
Fibrilação Atrial/etiologia , Fibrilação Atrial/genética , Proteínas de Homeodomínio/genética , Modelos Cardiovasculares , Fatores de Transcrição/genética , Animais , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/genética , Remodelamento Atrial/fisiologia , Padronização Corporal/genética , Simulação por Computador , Genes Homeobox , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Coração/embriologia , Proteínas de Homeodomínio/fisiologia , Humanos , Canais Iônicos/genética , Canais Iônicos/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , Mutação , Fatores de Transcrição/fisiologia
13.
Arch Insect Biochem Physiol ; 108(1): e21833, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34288091

RESUMO

The homeobox family is a large and diverse superclass of genes, many of which act as transcription factors that play important roles in tissue differentiation and embryogenesis in animals. The brown planthopper (BPH), Nilaparvata lugens, is the most destructive pest of rice in Asia, and high fecundity contributes significantly to its ecological success in natural and agricultural habits. Here, we identified 94 homeobox genes in BPH, which could be divided into 75 gene families and 9 classes. This number is comparable to the number of homeobox genes found in the honeybee Apis mellifera, but is slightly less than in Drosophila or the red flour beetle Tribolium castaneum. A spatio-temporal analysis indicated that most BPH homeobox genes were expressed in a development and tissue-specific manner, of which 21 genes were highly expressed in ovaries. RNA interference (RNAi)-mediated functional assay showed that 22 homeobox genes were important for nymph development and the nymph to adult transition, whereas 67 genes were dispensable during this process. Fecundity assay showed that knockdown of 13 ovary-biased genes (zfh1, schlank, abd-A, Lim3_2, Lmxb, Prop, ap_1, Not, lab, Hmx, vis, Pknox, and C15) led to the reproductive defect. This is the first comprehensive investigation into homeobox genes in a hemipteran insect and thus helps us to understand the functional significance of homeobox genes in insect reproduction.


Assuntos
Fertilidade/genética , Genes Homeobox , Hemípteros/genética , Animais , Perfilação da Expressão Gênica/métodos , Genes de Insetos , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Ninfa/genética , Controle de Pragas , Interferência de RNA , Reprodução/genética
15.
Dev Biol ; 479: 61-76, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34310923

RESUMO

Meis genes are known to play important roles in the hindbrain and neural crest cells of jawed vertebrates. To explore the roles of Meis genes in head development during evolution of vertebrates, we have identified four meis genes in the sea lamprey genome and characterized their patterns of expression and regulation, with a focus on the hindbrain and pharynx. Each of the lamprey meis genes displays temporally and spatially dynamic patterns of expression, some of which are coupled to rhombomeric domains in the developing hindbrain and select pharyngeal arches. Studies of Meis loci in mouse and zebrafish have identified enhancers that are bound by Hox and TALE (Meis and Pbx) proteins, implicating these factors in the direct regulation of Meis expression. We examined the lamprey meis loci and identified a series of cis-elements conserved between lamprey and jawed vertebrate meis genes. In transgenic reporter assays we demonstrated that these elements act as neural enhancers in lamprey embryos, directing reporter expression in appropriate domains when compared to expression of their associated endogenous meis gene. Sequence alignments reveal that these conserved elements are in similar relative positions of the meis loci and contain a series of consensus binding motifs for Hox and TALE proteins. This suggests that ancient Hox and TALE-responsive enhancers regulated expression of ancestral vertebrate meis genes in segmental domains in the hindbrain and have been retained in the meis loci during vertebrate evolution. The presence of conserved Meis, Pbx and Hox binding sites in these lamprey enhancers links Hox and TALE factors to regulation of lamprey meis genes in the developing hindbrain, indicating a deep ancestry for these regulatory interactions prior to the divergence of jawed and jawless vertebrates.


Assuntos
Lampreias/genética , Tubo Neural/embriologia , Rombencéfalo/embriologia , Animais , Sítios de Ligação , Padronização Corporal/genética , Sequência Conservada , Elementos Facilitadores Genéticos , Expressão Gênica/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Genes Homeobox/genética , Proteínas de Homeodomínio/metabolismo , Lampreias/metabolismo , Proteína Meis1/genética , Proteína Meis1/metabolismo , Crista Neural/metabolismo , Tubo Neural/metabolismo , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Fator de Transcrição 1 de Leucemia de Células Pré-B/metabolismo , Rombencéfalo/metabolismo , Fatores de Transcrição/metabolismo
16.
PLoS Genet ; 17(7): e1009649, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34228720

RESUMO

The differentiation efficiency of adult stem cells undergoes a significant decline in aged animals, which is closely related to the decline in organ function and age-associated diseases. However, the underlying mechanisms that ultimately lead to this observed decline of the differentiation efficiency of stem cells remain largely unclear. This study investigated Drosophila midguts and identified an obvious upregulation of caudal (cad), which encodes a homeobox transcription factor. This factor is traditionally known as a central regulator of embryonic anterior-posterior body axis patterning. This study reports that depletion of cad in intestinal stem/progenitor cells promotes quiescent intestinal stem cells (ISCs) to become activate and produce enterocytes in the midgut under normal gut homeostasis conditions. However, overexpression of cad results in the failure of ISC differentiation and intestinal epithelial regeneration after injury. Moreover, this study suggests that cad prevents intestinal stem/progenitor cell differentiation by modulating the Janus kinase/signal transducers and activators of the transcription pathway and Sox21a-GATAe signaling cascade. Importantly, the reduction of cad expression in intestinal stem/progenitor cells restrained age-associated gut hyperplasia in Drosophila. This study identified a function of the homeobox gene cad in the modulation of adult stem cell differentiation and suggested a potential gene target for the treatment of age-related diseases induced by age-related stem cell dysfunction.


Assuntos
Células-Tronco Adultas/metabolismo , Diferenciação Celular/genética , Proteínas de Drosophila/metabolismo , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição/metabolismo , Células-Tronco Adultas/fisiologia , Fatores Etários , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Genes Homeobox/genética , Proteínas de Homeodomínio/genética , Mucosa Intestinal/metabolismo , Intestinos/citologia , Janus Quinases/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética
17.
PLoS Genet ; 17(7): e1009681, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34280202

RESUMO

Long noncoding RNAs (lncRNAs) have been shown to play important roles in gene regulatory networks acting in early development. There has been rapid turnover of lncRNA loci during vertebrate evolution, with few human lncRNAs conserved beyond mammals. The sequences of these rare deeply conserved lncRNAs are typically not similar to each other. Here, we characterize HOXA-AS3 and HOXB-AS3, lncRNAs produced from the central regions of the HOXA and HOXB clusters. Sequence-similar orthologs of both lncRNAs are found in multiple vertebrate species and there is evident sequence similarity between their promoters, suggesting that the production of these lncRNAs predates the duplication of the HOX clusters at the root of the vertebrate lineage. This conservation extends to similar expression patterns of the two lncRNAs, in particular in cells transiently arising during early development or in the adult colon. Functionally, the RNA products of HOXA-AS3 and HOXB-AS3 regulate the expression of their overlapping HOX5-7 genes both in HT-29 cells and during differentiation of human embryonic stem cells. Beyond production of paralogous protein-coding and microRNA genes, the regulatory program in the HOX clusters therefore also relies on paralogous lncRNAs acting in restricted spatial and temporal windows of embryonic development and cell differentiation.


Assuntos
Proteínas de Homeodomínio/genética , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Células-Tronco Embrionárias/metabolismo , Endoderma/metabolismo , Enterócitos/metabolismo , Genes Homeobox , Proteínas de Homeodomínio/metabolismo , Humanos , Família Multigênica/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Homologia de Sequência , Vertebrados/genética
18.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072771

RESUMO

Recently, we documented a hematopoietic NKL-code mapping physiological expression patterns of NKL homeobox genes in human myelopoiesis including monocytes and their derived dendritic cells (DCs). Here, we enlarge this map to include normal NKL homeobox gene expressions in progenitor-derived DCs. Analysis of public gene expression profiling and RNA-seq datasets containing plasmacytoid and conventional dendritic cells (pDC and cDC) demonstrated HHEX activity in both entities while cDCs additionally expressed VENTX. The consequent aim of our study was to examine regulation and function of VENTX in DCs. We compared profiling data of VENTX-positive cDC and monocytes with VENTX-negative pDC and common myeloid progenitor entities and revealed several differentially expressed genes encoding transcription factors and pathway components, representing potential VENTX regulators. Screening of RNA-seq data for 100 leukemia/lymphoma cell lines identified prominent VENTX expression in an acute myelomonocytic leukemia cell line, MUTZ-3 containing inv(3)(q21q26) and t(12;22)(p13;q11) and representing a model for DC differentiation studies. Furthermore, extended gene analyses indicated that MUTZ-3 is associated with the subtype cDC2. In addition to analysis of public chromatin immune-precipitation data, subsequent knockdown experiments and modulations of signaling pathways in MUTZ-3 and control cell lines confirmed identified candidate transcription factors CEBPB, ETV6, EVI1, GATA2, IRF2, MN1, SPIB, and SPI1 and the CSF-, NOTCH-, and TNFa-pathways as VENTX regulators. Live-cell imaging analyses of MUTZ-3 cells treated for VENTX knockdown excluded impacts on apoptosis or induced alteration of differentiation-associated cell morphology. In contrast, target gene analysis performed by expression profiling of knockdown-treated MUTZ-3 cells revealed VENTX-mediated activation of several cDC-specific genes including CSFR1, EGR2, and MIR10A and inhibition of pDC-specific genes like RUNX2. Taken together, we added NKL homeobox gene activities for progenitor-derived DCs to the NKL-code, showing that VENTX is expressed in cDCs but not in pDCs and forms part of a cDC-specific gene regulatory network operating in DC differentiation and function.


Assuntos
Células Dendríticas/metabolismo , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Proteínas de Homeodomínio/genética , Linhagem Celular Tumoral , Biologia Computacional/métodos , Células Dendríticas/imunologia , Perfilação da Expressão Gênica , Genes Homeobox , Humanos , Imunofenotipagem , Transcriptoma
19.
Development ; 148(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34096572

RESUMO

Vertebrate Hox clusters are comprised of multiple Hox genes that control morphology and developmental timing along multiple body axes. Although results of genetic analyses using Hox-knockout mice have been accumulating, genetic studies in other vertebrates have not been sufficient for functional comparisons of vertebrate Hox genes. In this study, we isolated all of the seven hox cluster loss-of-function alleles in zebrafish using the CRISPR-Cas9 system. Comprehensive analysis of the embryonic phenotype and X-ray micro-computed tomography scan analysis of adult fish revealed several species-specific functional contributions of homologous Hox clusters along the appendicular axis, whereas important shared general principles were also confirmed, as exemplified by serial anterior vertebral transformations along the main body axis, observed in fish for the first time. Our results provide insights into discrete sub/neofunctionalization of vertebrate Hox clusters after quadruplication of the ancient Hox cluster. This set of seven complete hox cluster loss-of-function alleles provide a formidable resource for future developmental genetic analysis of the Hox patterning system in zebrafish.


Assuntos
Genes Homeobox/genética , Família Multigênica , Peixe-Zebra/genética , Peixe-Zebra/fisiologia , Animais , Sistemas CRISPR-Cas , Desenvolvimento Embrionário/genética , Evolução Molecular , Feminino , Duplicação Gênica , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Mutação , Esqueleto/anatomia & histologia , Esqueleto/crescimento & desenvolvimento , Especificidade da Espécie , Microtomografia por Raio-X , Peixe-Zebra/embriologia
20.
J Mol Evol ; 89(6): 396-414, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34097121

RESUMO

The majority of homeobox genes are highly conserved across animals, but the eutherian-specific ETCHbox genes, embryonically expressed and highly divergent duplicates of CRX, are a notable exception. Here we compare the ETCHbox genes of 34 mammalian species, uncovering dynamic patterns of gene loss and tandem duplication, including the presence of a large tandem array of LEUTX loci in the genome of the European rabbit (Oryctolagus cuniculus). Despite extensive gene gain and loss, all sampled species possess at least two ETCHbox genes, suggesting their collective role is indispensable. We find evidence for positive selection and show that TPRX1 and TPRX2 have been the subject of repeated gene conversion across the Boreoeutheria, homogenising their sequences and preventing divergence, especially in the homeobox region. Together, these results are consistent with a model where mammalian ETCHbox genes are dynamic in evolution due to functional overlap, yet have collective indispensable roles.


Assuntos
Conversão Gênica , Genes Homeobox , Animais , Evolução Molecular , Duplicação Gênica , Genes Homeobox/genética , Genoma/genética , Mamíferos/genética , Filogenia , Coelhos
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