RESUMO
In Arabidopsis thaliana, the transcription factors WRKY7, WRKY11 and WRKY17 act as negative defence regulators against Pseudomonas syringae pv. tomato (Pst) DC3000. However, their coordinated regulation of gene expression has yet to be fully explored. In this study, we conducted a transcriptomic analysis on the triple mutant wrky7/11/17 in response to Pst DC3000 at 0, 3 and 24 h post-inoculation (hpi). Our results suggest that at early infection stages (0 and 3 hpi), WRKY7, WRKY11 and WRKY17 significantly repress a group of genes involved in signal perception and transduction, including receptor-like kinases. Furthermore, at later stages of interaction (24 hpi), these transcription factors induce genes related to the biosynthesis and signalling of the jasmonic acid (JA) pathway. Further infection experiments with Pst DC3000 in plants treated with methyl jasmonate (a JA analogue) and infections with Botrytis cinerea, a pathogen against which JA-mediated responses are crucial for effective defence, support this proposal. Moreover, we analysed the role of WRKY7, WRKY11 and WRKY17 in alternative splicing regulation. A comparison between differentially expressed (DEG) and spliced (DAS) genes revealed that over 80% of DAS events do not occur in conjunction with overall changes in gene expression. Alternative splicing events were found in genes with functions in splicing and the JA pathway, such as ALY4, PRP40A, JAZ3 and JAZ10. These results suggest that WRKY7, WRKY11 and WRKY17 can also participate in this layer of gene expression regulation to modulate immunity negatively.
Assuntos
Processamento Alternativo , Proteínas de Arabidopsis , Arabidopsis , Botrytis , Ciclopentanos , Regulação da Expressão Gênica de Plantas , Oxilipinas , Doenças das Plantas , Pseudomonas syringae , Fatores de Transcrição , Pseudomonas syringae/patogenicidade , Oxilipinas/metabolismo , Oxilipinas/farmacologia , Arabidopsis/genética , Arabidopsis/microbiologia , Arabidopsis/imunologia , Ciclopentanos/metabolismo , Ciclopentanos/farmacologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Doenças das Plantas/microbiologia , Doenças das Plantas/genética , Processamento Alternativo/genética , Botrytis/patogenicidade , Transdução de Sinais/genética , Acetatos/farmacologia , Redes Reguladoras de GenesRESUMO
HER2-positive (HER2+) breast cancer is characterized by the overexpression of the ERBB2 (HER2) gene, which promotes aggressive tumor growth and poor prognosis. Targeting the ERBB2 pathway with single-agent therapies has shown limited efficacy due to resistance mechanisms and the complexity of gene interactions within the tumor microenvironment. This study aims to explore potential drug synergies by analyzing gene-drug interactions and combination therapies that target the ERBB2 pathway in HER2+ breast tumors. Using gene co-expression network analysis, we identified 23 metabolic pathways with significant cross-linking of gene interactions, including those involving EGFR tyrosine kinase inhibitors, PI3K, mTOR, and others. We visualized these interactions using Cytoscape to generate individual and combined drug-gene networks, focusing on frequently used drugs such as Erlotinib, Gefitinib, Lapatinib, and Cetuximab. Individual networks highlighted the direct effects of these drugs on their target genes and neighboring genes within the ERBB2 pathway. Combined drug networks, such as those for Cetuximab with Lapatinib, Cetuximab with Erlotinib, and Erlotinib with Lapatinib, revealed potential synergies that could enhance therapeutic efficacy by simultaneously influencing multiple genes and pathways. Our findings suggest that a network-based approach to analyzing drug combinations provides valuable insights into the molecular mechanisms of HER2+ breast cancer and offers promising strategies for overcoming drug resistance and improving treatment outcomes.
Assuntos
Neoplasias da Mama , Sinergismo Farmacológico , Redes Reguladoras de Genes , Receptor ErbB-2 , Transdução de Sinais , Humanos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Transdução de Sinais/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lapatinib/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cloridrato de Erlotinib/farmacologiaRESUMO
The neural crest (NC) is an embryonic cell population with high migratory capacity. It contributes to forming several organs and tissues, such as the craniofacial skeleton and the peripheral nervous system of vertebrates. Both pre-migratory and post-migratory NC cells are plastic, adopting multiple differentiation paths by responding to different inductive environmental signals. Cephalic neural crest cells (CNCCs) give rise to most of the cartilage and bone tissues in the head. On the other hand, the mesenchymal potential of trunk neural crest cells (TNCCs) is sparsely detected in some animal groups. The mesenchymal potential of TNCCs can be unveiled through specific environmental conditions of NC cultures. In this study, we present evidence that FGF8 treatment can foster increased chondrogenic differentiation of TNCCs, particularly during treatment at the migratory stage. Additionally, we conducted a transcriptomic analysis of TNCCs in the post-migratory stage, noting that exogenous FGF8 signaling can sustain multipotent status and, possibly, at the same time, a pro-cartilage regulatory gene network. Our results provide a more comprehensive understanding of the mechanisms underlying chondrogenic differentiation from TNCCs.
Assuntos
Diferenciação Celular , Condrogênese , Fator 8 de Crescimento de Fibroblasto , Redes Reguladoras de Genes , Crista Neural , Crista Neural/citologia , Crista Neural/metabolismo , Crista Neural/embriologia , Condrogênese/genética , Animais , Fator 8 de Crescimento de Fibroblasto/genética , Fator 8 de Crescimento de Fibroblasto/metabolismo , Diferenciação Celular/genética , Regulação da Expressão Gênica no Desenvolvimento , Embrião de Galinha , Movimento Celular , Transdução de SinaisRESUMO
BACKGROUND: Despite decades of research, an effective schistosomiasis vaccine remains elusive. The radiation-attenuated (RA) cercarial vaccine remains the best model for eliciting high levels of protection. We have recently explored this model in mice to identify potentially protective pathways by examining gene expression patterns in peripheral blood mononuclear cells (PBMC). METHODS: Herein, we reanalyzed the transcriptomic data from PBMC obtained from vaccinated and infected C57BL/6 mice in three timepoints (Days 7 and 17 after infection or vaccination and Day 7 post-challenge). In addition, we generated new data on PBMC collected 35 days after infection. Deconvolution analysis was performed to estimate immune cell composition by CIBERSORTx. Gene co-expression networks and over-representation analysis (ORA) were performed using the CEMiTool package. Protein-protein interaction networks were constructed using STRING, and the hub proteins for each module were identified using Cytoscape. RESULTS: Co-expression network analysis identified a module (M2) associated with the infection process, grouping genes related to a Th2 immune response, and a second module (M6) associated with the vaccination process, displaying pathways related to a Th1 response, CD8 + T cells and NK cells. Within each module, five hub proteins were identified based on protein-protein interaction networks. The M2 infection module revealed Chil3, Il4, Cx3cr1, Emr1 and Ccl2 as hubs, while module M6, associated with vaccination, disclosed Prf1, Klrc1, IFN-γ, Ncr1 and Tbx21 as hub proteins. CONCLUSIONS: Our data point to the potentiald role of NK cells that may contribute to the RA vaccine response through the production of IFN-γ orchestrated by the T-bet transcription factor (Tbx21).
Assuntos
Células Matadoras Naturais , Camundongos Endogâmicos C57BL , Schistosoma mansoni , Esquistossomose mansoni , Animais , Esquistossomose mansoni/prevenção & controle , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/parasitologia , Camundongos , Células Matadoras Naturais/imunologia , Schistosoma mansoni/imunologia , Schistosoma mansoni/genética , Vacinas Atenuadas/imunologia , Leucócitos Mononucleares/imunologia , Cercárias/imunologia , Cercárias/genética , Feminino , Perfilação da Expressão Gênica , Transcriptoma , Redes Reguladoras de Genes , VacinaçãoRESUMO
Congenital heart defects (CHDs) rank among the most common birth defects, presenting diverse phenotypes. Genetic and environmental factors are critical in molding the process of cardiogenesis. However, these factors' interactions are not fully comprehended. Hence, this study aimed to identify and characterize differentially expressed genes involved in CHD development through bioinformatics pipelines. We analyzed experimental datasets available in genomic databases, using transcriptome, gene enrichment, and systems biology strategies. Network analysis based on genetic and phenotypic ontologies revealed that EP300, CALM3, and EGFR genes facilitate rapid information flow, while NOTCH1, TNNI3, and SMAD4 genes are significant mediators within the network. Differential gene expression (DGE) analysis identified 2513 genes across three study types, (1) Tetralogy of Fallot (ToF); (2) Hypoplastic Left Heart Syndrome (HLHS); and (3) Trisomy 21/CHD, with LYVE1, PLA2G2A, and SDR42E1 genes found in three of the six studies. Interaction networks between genes from ontology searches and the DGE analysis were evaluated, revealing interactions in ToF and HLHS groups, but none in Trisomy 21/CHD. Through enrichment analysis, we identified immune response and energy generation as some of the relevant ontologies. This integrative approach revealed genes not previously associated with CHD, along with their interactions and underlying biological processes.
Assuntos
Biologia Computacional , Redes Reguladoras de Genes , Cardiopatias Congênitas , Humanos , Biologia Computacional/métodos , Cardiopatias Congênitas/genética , Perfilação da Expressão Gênica , Transcriptoma/genética , Ontologia GenéticaRESUMO
Leishmania spp. commonly infects phagocytic cells of the immune system, particularly macrophages, employing various immune evasion strategies that enable their survival by altering the intracellular environment. In mammals, these parasites establish persistent infections by modulating gene expression in macrophages, thus interfering with immune signaling and response pathways, ultimately creating a favorable environment for the parasite's survival and reproduction. In this study, our objective was to use data mining and subsequent filtering techniques to identify the genes that play a crucial role in the infection process of Leishmania spp. We aimed to pinpoint genes that have the potential to influence the progression of Leishmania infection. To achieve this, we exploited prior, curated knowledge from major databases and constructed 16 datasets of human molecular information consisting of coding genes and corresponding proteins. We obtained over 400 proteins, identifying approximately 200 genes. The proteins coded by these genes were subsequently used to build a network of protein-protein interactions, which enabled the identification of key players; we named this set Predicted Genes. Then, we selected approximately 10% of Predicted Genes for biological validation. THP-1 cells, a line of human macrophages, were infected with Leishmania major in vitro for the validation process. We observed that L. major has the capacity to impact crucial genes involved in the immune response, resulting in macrophage inactivation and creating a conducive environment for the survival of Leishmania parasites.
Assuntos
Leishmania major , Macrófagos , Humanos , Leishmania major/genética , Macrófagos/parasitologia , Macrófagos/metabolismo , Redes Reguladoras de Genes , Mapas de Interação de Proteínas/genética , Células THP-1 , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/imunologia , Regulação da Expressão Gênica , Mineração de DadosRESUMO
Breast cancer is a heterogeneous disease comprising various subtypes with distinct molecular characteristics, clinical outcomes, and therapeutic responses. This heterogeneity evidences significant challenges for diagnosis, prognosis, and treatment. Traditional genomic co-expression network analyses often overlook individual-specific interactions critical for personalized medicine. In this study, we employed single-sample gene co-expression network analysis to investigate the structural and functional genomic alterations across breast cancer subtypes (Luminal A, Luminal B, Her2-enriched, and Basal-like) and compared them with normal breast tissue. We utilized RNA-Seq gene expression data to infer gene co-expression networks. The LIONESS algorithm allowed us to construct individual networks for each patient, capturing unique co-expression patterns. We focused on the top 10,000 gene interactions to ensure consistency and robustness in our analysis. Network metrics were calculated to characterize the topological properties of both aggregated and single-sample networks. Our findings reveal significant fragmentation in the co-expression networks of breast cancer subtypes, marked by a change from interchromosomal (TRANS) to intrachromosomal (CIS) interactions. This transition indicates disrupted long-range genomic communication, leading to localized genomic regulation and increased genomic instability. Single-sample analyses confirmed that these patterns are consistent at the individual level, highlighting the molecular heterogeneity of breast cancer. Despite these pronounced alterations, the proportion of CIS interactions did not significantly correlate with patient survival outcomes across subtypes, suggesting limited prognostic value. Furthermore, we identified high-degree genes and critical cytobands specific to each subtype, providing insights into subtype-specific regulatory networks and potential therapeutic targets. These genes play pivotal roles in oncogenic processes and may represent important keys for targeted interventions. The application of single-sample co-expression network analysis proves to be a powerful tool for uncovering individual-specific genomic interactions.
Assuntos
Neoplasias da Mama , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/classificação , Feminino , Perfilação da Expressão Gênica/métodos , Prognóstico , Biomarcadores Tumorais/genética , AlgoritmosRESUMO
Peripheral regulation emerges as a promising intervention in the early stages of Alzheimer's disease (AD). The hub genes in the peripheral blood of MCI patients from GEO database (GSE63060, GSE63061) were screened using weighted gene co-expression analysis (WGCNA). Meanwhile, behavioral tests, HE staining and Nissl staining were used to detect the memory impairment and histopathological changes in 24-week-old male 3×Tg-AD mice. Thioflavin-S and immunohistochemical staining were used to determine the Aß deposition in both intracellular and extracellular neurons. Subsequently, the MCI-hub genes were verified by quantitative real-time PCR (qRT-PCR) in the peripheral blood of 3×Tg-AD mice. The research revealed ten hub genes associated with MCI were identified WGCNA. Short-term memory loss, intracellular Aß deposition and limited of extracellular amyloid plaques in 3×Tg-AD mice. The qRT-PCR analysis of peripheral blood from these mice revealed significantly down-regulation in the expression levels of ATP5C1, ITGB2, EFTUD2 and RPS27A genes; whereas the expression level of VCP gene was significantly up-regulated. These findings confirmed that 24-week-old male 3×Tg-AD mice were a valuable animal model for simulating the early symptomatic stages of AD. Additionally, the peripheral blood MCI-hub genes related to immune response, energy metabolism and ribosomal coding efficiency provide potential biomarkers for this stage.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Camundongos Transgênicos , Proteínas tau , Animais , Doença de Alzheimer/genética , Doença de Alzheimer/sangue , Masculino , Camundongos , Proteínas tau/genética , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genética , Reação em Cadeia da Polimerase em Tempo Real , Redes Reguladoras de GenesRESUMO
Drought stress is a key limitation for plant growth and colonization of arid habitats. We study the evolution of gene expression response to drought stress in a wild tomato, Solanum chilense, naturally occurring in dry habitats in South America. We conduct a transcriptome analysis under standard and drought experimental conditions to identify drought-responsive gene networks and estimate the age of the involved genes. We identify two main regulatory networks corresponding to two typical drought-responsive strategies: cell cycle and fundamental metabolic processes. The metabolic network exhibits a more recent evolutionary origin and a more variable transcriptome response than the cell cycle network (with ancestral origin and higher conservation of the transcriptional response). We also integrate population genomics analyses to reveal positive selection signals acting at the genes of both networks, revealing that genes exhibiting selective sweeps of older age also exhibit greater connectivity in the networks. These findings suggest that adaptive changes first occur at core genes of drought response networks, driving significant network re-wiring, which likely underpins species divergence and further spread into drier habitats. Combining transcriptomics and population genomics approaches, we decipher the timing of gene network evolution for drought stress response in arid habitats.
Assuntos
Secas , Redes Reguladoras de Genes , Solanum , Estresse Fisiológico , Solanum/genética , Estresse Fisiológico/genética , Transcriptoma/genética , Adaptação Fisiológica/genética , Perfilação da Expressão Gênica , Ecossistema , Evolução Molecular , Regulação da Expressão Gênica de Plantas , América do Sul , Seleção GenéticaRESUMO
Gonadal sex determination (GSD) is a complex but poorly understood process in the early stages of embryonic development. This process determines whether the bipotential gonadal primordium (BGP) will differentiate into testes or ovaries through the activation of genetic factors related to Sertoli or Granulosa cells, respectively. The study of this developmental process remains challenging due to experimental limitations and the complexity of the underlying genetic interactions. Boolean Networks (BNs) are binary networks that simulate genetic behavior and are commonly used for modeling gene regulatory networks (GRNs) due to their simplicity when dealing with a high number of gene interactions. Reported BNs usually use a synchronous (parallel) update scheme, which means that all the nodes (representing genes) update their values simultaneously. However, the use of this update scheme has been criticized because it cannot represent biological systems that are highly regulated at a temporal scale. Asynchronous and block-sequential updating schemes appear as an alternative to tackle this issue. In the first case, the updating scheme follows a random behavior while, in the second case, the set of network nodes is partitioned into blocks such that the nodes within a block are updated simultaneously, and the blocks are considered in a specific order sequence. To assess the impact of different updating approaches in a GRN associated to GSD we first made a node reduction without losing the main dynamics of the original network which are related to the formation of testes and ovaries. Then, we tested the effect of perturbations given by the inactivation of genes on the network attractors, specifically the SRY and WNT4 genes, since the former is only present in the Y chromosome and the latter is of importance in early embryo development. We found that both genes were crucial, but WNT4 alone showed a higher percentage of attractors towards a phenotype than the SRY alone. Finally, we found that using asynchronous and block-sequential updating schemes, the attraction basins - i.e., the set of configurations that reach an attractor - remain with similar percentages to those of the original network, which supports the robustness of the model.
Assuntos
Redes Reguladoras de Genes , Processos de Determinação Sexual , Humanos , Processos de Determinação Sexual/genética , Feminino , Masculino , Ovário/metabolismo , Testículo/metabolismo , Gônadas/metabolismo , Modelos GenéticosRESUMO
Hepatitis C virus (HCV) infection poses a significant public health challenge and often leads to long-term health complications and even death. Parkinson's disease (PD) is a progressive neurodegenerative disorder with a proposed viral etiology. HCV infection and PD have been previously suggested to be related. This work aimed to identify potential biomarkers and pathways that may play a role in the joint development of PD and HCV infection. Using BioOptimatics-bioinformatics driven by mathematical global optimization-, 22 publicly available microarray and RNAseq datasets for both diseases were analyzed, focusing on sex-specific differences. Our results revealed that 19 genes, including MT1H, MYOM2, and RPL18, exhibited significant changes in expression in both diseases. Pathway and network analyses stratified by sex indicated that these gene expression changes were enriched in processes related to immune response regulation in females and immune cell activation in males. These findings suggest a potential link between HCV infection and PD, highlighting the importance of further investigation into the underlying mechanisms and potential therapeutic targets involved.
Assuntos
Hepatite C , Doença de Parkinson , Feminino , Humanos , Masculino , Biomarcadores , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/virologia , Doença de Parkinson/genética , Doença de Parkinson/virologia , Fatores SexuaisRESUMO
BACKGROUND: Cervical cancer has a high incidence and mortality rate, affecting more than half a million women in 2018. Its development is strongly related to high-risk HPV infection. After infection, several cellular molecules are affected, including microRNAs (miRNAs), which are the focus of our study. We aimed to investigate changes in microRNA expression associated with cervical cancer and analyze the biological significance of these changes induced by HPV proteins. METHODS: We analyzed transcriptome data retrieved from the NCBI website to investigate miRNA and gene expression in cervical cancer. We evaluated the alteration in expression of miRNAs and genes (between normal tissues and cervical cancer) using the GEO2R tool and selected those with significantly altered expression (p-value < 0.05). The target genes of miRNAs were predicted using the miRNA Pathway Dictionary Database. Subsequently, we created a network of biological pathways affected by miRNA deregulation using Cytoscape software and associated the altered miRNAs with the Hallmarks of Cancer using COSMIC v84. RESULTS: We identified 10 miRNAs and 82 target genes with significantly altered expression levels in cervical cancer that matched the predicted results. In addition, the deregulation of these genes causes changes in 52 biological pathways. These miRNAs affected pathways such as interferon signaling (miR-106b-5p and miR-1183), signaling by interleukins (miR-557, miR-106b-5p, miR-15a-5p, and miR-21-5p), oxidative stress-induced senescence (miR-557 and miR-15a-5p), cell cycle checkpoints (miR-557), transcriptional regulation by P53 (miR-557 and miR-15a-5p), and the exchange of oxygen and carbon dioxide in erythrocytes (miR-15a-5p). CONCLUSION: Alterations in miRNA expression play an important role in the pathogenesis of cervical cancer, affecting several biological pathways and Hallmarks of Cancer, such as immune system regulation, cell cycle regulation, and energy metabolism. Thus, their analysis can contribute to the development of diagnostic and prognostic biomarkers and more effective treatments for cervical cancer.
Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , MicroRNAs/genética , Feminino , Redes Reguladoras de Genes , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/genética , Perfilação da Expressão Gênica , Transcriptoma , PrognósticoRESUMO
Pediatric adrenocortical tumors (ACTs), rare conditions with uncertain prognoses, have high incidence in southern and southeastern Brazil. Pediatric ACTs are highly heterogeneous, so establishing prognostic markers for these tumors is challenging. We have conducted transcriptomic analysis on 14 pediatric ACT samples and compared cases with favorable and unfavorable clinical outcomes to identify prognostically significant genes. This comparison showed 1257 differentially expressed genes in favorable and unfavorable cases. Among these genes, 15 out of 60 hub genes were significantly associated with five-year event-free survival (EFS), and 10 had significant diagnostic value for predicting ACT outcomes in an independent microarray dataset of pediatric adrenocortical carcinomas (GSE76019). Overexpression of N4BP2, HSPB6, JUN, APBB1IP, STK17B, CSNK1D, and KDM3A was associated with poorer EFS, whereas lower expression of ISCU, PTPR, PRKAB2, CD48, PRF1, ITGAL, KLK15, and HIST1H3J was associated with worse outcomes. Collectively, these findings underscore the prognostic significance of these hub genes and suggest that they play a potential role in pediatric ACT progression and are useful predictors of clinical outcomes.
Assuntos
Neoplasias do Córtex Suprarrenal , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/mortalidade , Prognóstico , Criança , Feminino , Masculino , Pré-Escolar , Perfilação da Expressão Gênica , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/mortalidade , Análise de Sequência de RNA/métodos , Adolescente , Biomarcadores Tumorais/genética , Redes Reguladoras de Genes , Transcriptoma/genética , LactenteRESUMO
We presented a method to find potential cancer attractors using single-cell RNA sequencing (scRNA-seq) data. We tested our method in a Glioblastoma Multiforme (GBM) dataset, an aggressive brain tumor presenting high heterogeneity. Using the cancer attractor concept, we argued that the GBM's underlying dynamics could partially explain the observed heterogeneity, with the dataset covering a representative region around the attractor. Exploratory data analysis revealed promising GBM's cellular clusters within a 3-dimensional marker space. We approximated the clusters' centroid as stable states and each cluster covariance matrix as defining confidence regions. To investigate the presence of attractors inside the confidence regions, we constructed a GBM gene regulatory network, defined a model for the dynamics, and prepared a framework for parameter estimation. An exploration of hyperparameter space allowed us to sample time series intending to simulate myriad variations of the tumor microenvironment. We obtained different densities of stable states across gene expression space and parameters displaying multistability across different clusters. Although we used our methodological approach in studying GBM, we would like to highlight its generality to other types of cancer. Therefore, this report contributes to an advance in the simulation of cancer dynamics and opens avenues to investigate potential therapeutic targets.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Análise de Sequência de RNA , Análise de Célula Única , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Análise de Célula Única/métodos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Análise de Sequência de RNA/métodos , Simulação por Computador , Redes Reguladoras de Genes , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral/genética , Perfilação da Expressão Gênica/métodos , Biologia Computacional/métodosRESUMO
Periodontal disease, a multifactorial inflammatory condition affecting the supporting structures of the teeth, has been increasingly recognized for its association with various systemic diseases. Understanding the molecular comorbidities of periodontal disease is crucial for elucidating shared pathogenic mechanisms and potential therapeutic targets. In this study, we conducted comprehensive literature and biological database mining by utilizing DisGeNET2R for extracting gene-disease associations, Romin for integrating and modeling molecular interaction networks, and Rentrez R libraries for accessing and retrieving relevant information from NCBI databases. This integrative bioinformatics approach enabled us to systematically identify diseases sharing associated genes, proteins, or molecular pathways with periodontitis. Our analysis revealed significant molecular overlaps between periodontal disease and several systemic conditions, including cardiovascular diseases, diabetes mellitus, rheumatoid arthritis, and inflammatory bowel diseases. Shared molecular mechanisms implicated in the pathogenesis of these diseases and periodontitis encompassed dysregulation of inflammatory mediators, immune response pathways, oxidative stress pathways, and alterations in the extracellular matrix. Furthermore, network analysis unveiled the key hub genes and proteins (such as TNF, IL6, PTGS2, IL10, NOS3, IL1B, VEGFA, BCL2, STAT3, LEP and TP53) that play pivotal roles in the crosstalk between periodontal disease and its comorbidities, offering potential targets for therapeutic intervention. Insights gained from this integrative approach shed light on the intricate interplay between periodontal health and systemic well-being, emphasizing the importance of interdisciplinary collaboration in developing personalized treatment strategies for patients with periodontal disease and associated comorbidities.
Assuntos
Comorbidade , Redes Reguladoras de Genes , Doenças Periodontais , Humanos , Doenças Periodontais/genética , Doenças Periodontais/epidemiologia , Mapas de Interação de Proteínas/genética , Biologia Computacional/métodos , Periodontite/genética , Periodontite/epidemiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/epidemiologia , Artrite Reumatoide/genética , Artrite Reumatoide/epidemiologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/epidemiologiaRESUMO
Background: The diagnosis and treatment of lung, colon, and gastric cancer through the histologic characteristics and genomic biomarkers have not had a strong impact on the mortality rates of the top three global causes of death by cancer. Methods: Twenty-five transcriptomic analyses (10 lung cancer, 10 gastric cancer, and 5 colon cancer datasets) followed our own bioinformatic pipeline based on the utilization of specialized libraries from the R language and DAVID´s gene enrichment analyses to identify a regulatory metafirm network of transcription factors and target genes common in every type of cancer, with experimental evidence that supports its relationship with the unlocking of cell phenotypic plasticity for the acquisition of the hallmarks of cancer during the tumoral process. The network's regulatory functional and signaling pathways might depend on the constant crosstalk with the microbiome network established in the oral-gut-lung axis. Results: The global transcriptomic network analysis highlighted the impact of transcription factors (SOX4, TCF3, TEAD4, ETV4, and FOXM1) that might be related to stem cell programming and cancer progression through the regulation of the expression of genes, such as cancer-cell membrane receptors, that interact with several microorganisms, including human T-cell leukemia virus 1 (HTLV-1), the human papilloma virus (HPV), the Epstein-Barr virus (EBV), and SARS-CoV-2. These interactions can trigger the MAPK, non-canonical WNT, and IFN signaling pathways, which regulate key transcription factor overexpression during the establishment and progression of lung, colon, and gastric cancer, respectively, along with the formation of the microbiome network. Conclusion: The global transcriptomic network analysis highlights the important interaction between key transcription factors in lung, colon, and gastric cancer, which regulates the expression of cancer-cell membrane receptors for the interaction with the microbiome network during the tumorigenic process.
Assuntos
Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Transcriptoma , Humanos , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Biologia Computacional , Pulmão/microbiologia , Pulmão/patologia , Boca/microbiologia , Transdução de Sinais , Microbioma Gastrointestinal/genética , Microbiota/genética , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/genética , Regulação Neoplásica da Expressão GênicaRESUMO
To further understand the impact of deficiency of the autoimmune regulator (Aire) gene during the adhesion of medullary thymic epithelial cells (mTECs) to thymocytes, we sequenced single-cell libraries (scRNA-seq) obtained from Aire wild-type (WT) (Airewt/wt ) or Aire-deficient (Airewt/mut ) mTECs cocultured with WT single-positive (SP) CD4+ thymocytes. Although the libraries differed in their mRNA and long noncoding RNA (lncRNA) profiles, indicating that mTECs were heterogeneous in terms of their transcriptome, UMAP clustering revealed that both mTEC lines expressed their specific markers, i.e., Epcam, Itgb4, Itga6, and Casp3 in resting mTECs and Ccna2, Pbk, and Birc5 in proliferative mTECs. Both cocultured SP CD4+ thymocytes remained in a homogeneous cluster expressing the Il7r and Ccr7 markers. Comparisons of the two types of cocultures revealed the differential expression of mRNAs that encode transcription factors (Zfpm2, Satb1, and Lef1), cell adhesion genes (Itgb1) in mTECs, and Themis in thymocytes, which is associated with the regulation of positive and negative selection. At the single-cell sequencing resolution, we observed that Aire acts on both Aire WT and Aire-deficient mTECs as an upstream controller of mRNAs, which encode transcription factors or adhesion proteins that, in turn, are posttranscriptionally controlled by lncRNAs, for example, Neat1, Malat1, Pvt1, and Dancr among others. Under Aire deficiency, mTECs dysregulate the expression of MHC-II, CD80, and CD326 (EPCAM) protein markers as well as metabolism and cell cycle-related mRNAs, which delay the cell cycle progression. Moreover, when adhered to mTECs, WT SP CD4+ or CD8+ thymocytes modulate the expression of cell activation proteins, including CD28 and CD152/CTLA4, and the expression of cellular metabolism mRNAs. These findings indicate a complex mechanism through which an imbalance in Aire expression can affect mTECs and thymocytes during adhesion.
Assuntos
Proteína AIRE , Adesão Celular , Células Epiteliais , RNA Longo não Codificante , Timócitos , Fatores de Transcrição , Transcriptoma , RNA Longo não Codificante/genética , Animais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Camundongos , Timócitos/metabolismo , Timócitos/imunologia , Timócitos/citologia , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Timo/citologia , Timo/imunologia , Timo/metabolismo , Análise de Célula Única , Redes Reguladoras de Genes , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Técnicas de Cocultura , Perfilação da Expressão Gênica , Camundongos KnockoutRESUMO
Chilean peach growers have achieved worldwide recognition for their high-quality fruit products. Among the main factors influencing peach fruit quality, sweetness is pivotal for maintaining the market's competitiveness. Numerous studies have been conducted in different peach-segregating populations to unravel SSC regulation. However, different cultivars may also have distinct genetic conformation, and other factors, such as environmental conditions, can significantly impact SSC. Using a transcriptomic approach with a gene co-expression network analysis, we aimed to identify the regulatory mechanism that controls the sugar accumulation process in an 'O × N' peach population. This population was previously studied through genomic analysis, associating LG5 with the genetic control of the SSC trait. The results obtained in this study allowed us to identify 91 differentially expressed genes located on chromosome 5 of the peach genome as putative new regulators of sugar accumulation in peach, together with a regulatory network that involves genes directly associated with sugar transport (PpSWEET15), cellulose biosynthesis (PpCSLG2), flavonoid biosynthesis (PpPAL1), pectin modifications (PpPG, PpPL and PpPMEi), expansins (PpEXPA1 and PpEXPA8) and several transcription factors (PpC3H67, PpHB7, PpRVE1 and PpCBF4) involved with the SSC phenotype. These results contribute to a better understanding of the genetic control of the SSC trait for future breeding programs in peaches.
Assuntos
Frutas , Redes Reguladoras de Genes , Prunus persica , Prunus persica/genética , Prunus persica/metabolismo , Frutas/genética , Frutas/metabolismo , Redes Reguladoras de Genes/genética , Regulação da Expressão Gênica de Plantas/genética , Açúcares/metabolismo , Perfilação da Expressão Gênica , ChileRESUMO
This study aimed to perform exhaustive bioinformatic analysis by using GSE29221 micro-array maps obtained from healthy controls and Type 2 Diabetes (T2DM) patients. Raw data are downloaded from the Gene Expression Omnibus database and processed by the limma package in R software to identify Differentially Expressed Genes (DEGs). Gene ontology functional analysis and Kyoto Gene Encyclopedia and Genome Pathway analysis are performed to determine the biological functions and pathways of DEGs. A protein interaction network is constructed using the STRING database and Cytoscape software to identify key genes. Finally, immune infiltration analysis is performed using the Cibersort method. This study has implications for understanding the underlying molecular mechanism of T2DM and provides potential targets for further research.
Assuntos
Biologia Computacional , Diabetes Mellitus Tipo 2 , Perfilação da Expressão Gênica , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Mapas de Interação de Proteínas/genética , Redes Reguladoras de Genes/genética , Ontologia Genética , Bases de Dados Genéticas , Estudos de Casos e ControlesRESUMO
Comprehension of the genetic basis of temperament has been improved by recent advances in the identification of genes and genetic variants. However, due to the complexity of the temperament traits, the elucidation of the genetic architecture of temperament is incomplete. A systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to analyze candidate genes related to bovine temperament, using bovine as the population, SNPs and genes as the exposure, and temperament test as the outcome, as principal search terms for population, exposure, and outcome (PEO) categories to define the scope of the search. The search results allowed the selection of 36 articles after removing duplicates and filtering by relevance. One hundred-two candidate genes associated with temperament traits were identified. The genes were further analyzed to construct an interaction network using the STRING database, resulting in 113 nodes and 346 interactions and the identification of 31 new candidate genes for temperament. Notably, the main genes identified were SST and members of the Kelch family. The candidate genes displayed interactions with pathways associated with different functions such as AMPA receptors, hormones, neuronal maintenance, protein signaling, neuronal regulation, serotonin synthesis, splicing, and ubiquitination activities. These new findings demonstrate the complexity of interconnected biological processes that regulate behavior and stress response in mammals. This insight now enables our targeted analysis of these newly identified temperament candidate genes in bovines.