RESUMEN

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.

Asunto(s)

Hepatitis C , Enfermedad de Parkinson , Femenino , Humanos , Masculino , Biomarcadores , Biología Computacional/métodos , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Hepacivirus/genética , Hepatitis C/complicaciones , Hepatitis C/virología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/virología , Factores Sexuales

RESUMEN

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.

Asunto(s)

Sequías , Redes Reguladoras de Genes , Solanum , Estrés Fisiológico , Solanum/genética , Estrés Fisiológico/genética , Transcriptoma/genética , Adaptación Fisiológica/genética , Perfilación de la Expresión Génica , Ecosistema , Evolución Molecular , Regulación de la Expresión Génica de las Plantas , América del Sur , Selección Genética

RESUMEN

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.

Asunto(s)

Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Ratones Transgénicos , Proteínas tau , Animales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/sangre , Masculino , Ratones , Proteínas tau/genética , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Redes Reguladoras de Genes

RESUMEN

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.

Asunto(s)

Frutas , Redes Reguladoras de Genes , Prunus persica , Prunus persica/genética , Prunus persica/metabolismo , Frutas/genética , Frutas/metabolismo , Redes Reguladoras de Genes/genética , Regulación de la Expresión Génica de las Plantas/genética , Azúcares/metabolismo , Perfilación de la Expresión Génica , Chile

RESUMEN

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.

Asunto(s)

Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Transcriptoma , Humanos , Neoplasias Pulmonares/microbiología , Neoplasias Pulmonares/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Biología Computacional , Pulmón/microbiología , Pulmón/patología , Boca/microbiología , Transducción de Señal , Microbioma Gastrointestinal/genética , Microbiota/genética , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/genética , Regulación Neoplásica de la Expresión Génica

RESUMEN

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.

Asunto(s)

Proteína AIRE , Adhesión Celular , Células Epiteliales , ARN Largo no Codificante , Timocitos , Factores de Transcripción , Transcriptoma , ARN Largo no Codificante/genética , Animales , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ratones , Timocitos/metabolismo , Timocitos/inmunología , Timocitos/citología , Células Epiteliales/metabolismo , Células Epiteliales/inmunología , Timo/citología , Timo/inmunología , Timo/metabolismo , Análisis de la Célula Individual , Redes Reguladoras de Genes , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Técnicas de Cocultivo , Perfilación de la Expresión Génica , Ratones Noqueados

RESUMEN

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.

Asunto(s)

Comorbilidad , Redes Reguladoras de Genes , Enfermedades Periodontales , Humanos , Enfermedades Periodontales/genética , Enfermedades Periodontales/epidemiología , Mapas de Interacción de Proteínas/genética , Biología Computacional/métodos , Periodontitis/genética , Periodontitis/epidemiología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/epidemiología , Artritis Reumatoide/genética , Artritis Reumatoide/epidemiología , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/epidemiología

RESUMEN

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.

Asunto(s)

Redes Reguladoras de Genes , Polimorfismo de Nucleótido Simple , Temperamento , Bovinos/genética , Animales , Mapas de Interacción de Proteínas/genética

RESUMEN

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.

Asunto(s)

Biología Computacional , Diabetes Mellitus Tipo 2 , Perfilación de la Expresión Génica , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/inmunología , Mapas de Interacción de Proteínas/genética , Redes Reguladoras de Genes/genética , Ontología de Genes , Bases de Datos Genéticas , Estudios de Casos y Controles

RESUMEN

Ligand-receptor systems, covalent modification cycles, and transcriptional networks are the fundamental components of cell signaling and gene expression systems. While their behavior in reaching a steady-state regime under step-like stimulation is well understood, their response under repetitive stimulation, particularly at early time stages is poorly characterized. Yet, early-stage responses to external inputs are arguably as informative as late-stage ones. In simple systems, a periodic stimulation elicits an initial transient response, followed by periodic behavior. Transient responses are relevant when the stimulation has a limited time span, or when the stimulated component's timescale is slow as compared to the timescales of the downstream processes, in which case the latter processes may be capturing only those transients. In this study, we analyze the frequency response of simple motifs at different time stages. We use dose-conserved pulsatile input signals and consider different metrics versus frequency curves. We show that in ligand-receptor systems, there is a frequency preference response in some specific metrics during the transient stages, which is not present in the periodic regime. We suggest this is a general system-level mechanism that cells may use to filter input signals that have consequences for higher order circuits. In addition, we evaluate how the described behavior in isolated motifs is reflected in similar types of responses in cascades and pathways of which they are a part. Our studies suggest that transient frequency preferences are important dynamic features of cell signaling and gene expression systems, which have been overlooked.

Asunto(s)

Transducción de Señal , Transducción de Señal/fisiología , Transducción de Señal/genética , Modelos Biológicos , Ligandos , Biología de Sistemas/métodos , Redes Reguladoras de Genes/genética

RESUMEN

Breast cancer, characterized by its complexity and diversity, presents significant challenges in understanding its underlying biology. In this study, we employed gene co-expression network analysis to investigate the gene composition and functional patterns in breast cancer subtypes and normal breast tissue. Our objective was to elucidate the detailed immunological features distinguishing these tumors at the transcriptional level and to explore their implications for diagnosis and treatment. The analysis identified nine distinct gene module clusters, each representing unique transcriptional signatures within breast cancer subtypes and normal tissue. Interestingly, while some clusters exhibited high similarity in gene composition between normal tissue and certain subtypes, others showed lower similarity and shared traits. These clusters provided insights into the immune responses within breast cancer subtypes, revealing diverse immunological functions, including innate and adaptive immune responses. Our findings contribute to a deeper understanding of the molecular mechanisms underlying breast cancer subtypes and highlight their unique characteristics. The immunological signatures identified in this study hold potential implications for diagnostic and therapeutic strategies. Additionally, the network-based approach introduced herein presents a valuable framework for understanding the complexities of other diseases and elucidating their underlying biology.

Asunto(s)

Neoplasias de la Mama , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Inflamación , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Femenino , Inflamación/inmunología , Inflamación/genética , Transcriptoma , Biomarcadores de Tumor/genética

RESUMEN

Feed cost represents a major economic determinant within cattle production, amounting to an estimated 75% of the total variable costs. Consequently, comprehensive approaches such as optimizing feed utilization through alternative feed sources, alongside the selection of feed-efficient animals, are of great significance. Here, we investigate the effect of two diets, traditional corn-grain fed and alternative by-product based, on 14 phenotypes related to feed, methane emission and production efficiency and on multi-tissue transcriptomics data from liver, muscle, and rumen wall, derived from 52 Nellore bulls, 26 on each diet. To this end, diets were contrasted at the level of phenotype, gene expression, and gene-phenotype network connectivity. As regards the phenotypic level, at a P value < 0.05, significant differences were found in favour of the alternative diet for average daily weight gain at finishing, dry matter intake at finishing, methane emission, carcass yield and subcutaneous fat thickness at the rib-eye muscle area. In terms of the transcriptional level of the 14,776 genes expressed across the examined tissues, we found 487, 484, and 499 genes differentially expressed due to diet in liver, muscle, and rumen, respectively (P value < 0.01). To explore differentially connected phenotypes across both diet-based networks, we focused on the phenotypes with the largest change in average number of connections within diets and tissues, namely methane emission and carcass yield, highlighting, in particular, gene expression changes involving SREBF2, and revealing the largest differential connectivity in rumen and muscle, respectively. Similarly, from examination of differentially connected genes across diets, the top-ranked most differentially connected regulators within each tissue were MEOX1, PTTG1, and BASP1 in liver, muscle, and rumen, respectively. Changes in gene co-expression patterns suggest activation or suppression of specific biological processes and pathways in response to dietary interventions, consequently impacting the phenotype. The identification of genes that respond differently to diets and their associated phenotypic effects serves as a crucial stepping stone for further investigations, aiming to build upon our discoveries. Ultimately, such advancements hold the promise of improving animal welfare, productivity, and sustainability in livestock farming.

Asunto(s)

Alimentación Animal , Dieta , Hígado , Rumen , Animales , Bovinos/genética , Hígado/metabolismo , Rumen/metabolismo , Alimentación Animal/análisis , Dieta/veterinaria , Transcriptoma , Masculino , Músculo Esquelético/metabolismo , Fenotipo , Redes Reguladoras de Genes , Perfilación de la Expresión Génica

RESUMEN

Ariel Waisman is a CONICET Junior Researcher in the Laboratory of Applied Research in Neurosciences at FLENI in Buenos Aires, Argentina. Ariel's group studies gene regulatory networks in human pluripotent stem cells to address mechanisms of development and cardiac differentiation, among other topics. We spoke to Ariel over Teams to learn more about his career path, the research interests in his group, and the challenges faced by researchers in Argentina and the Global South.

Asunto(s)

Biología Evolutiva , Humanos , Historia del Siglo XXI , Historia del Siglo XX , Argentina , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Diferenciación Celular , Redes Reguladoras de Genes , Neurociencias

RESUMEN

Multiple sclerosis (MS) is a common disease in young women of reproductive age, characterized by demyelination of the central nervous system (CNS). Understanding how genes related to MS are expressed during pregnancy can provide insights into the potential mechanisms by which pregnancy affects the course of this disease. This review article presents evidence-based studies on these patients' gene expression patterns. In addition, it constructs interaction networks using bioinformatics tools, such as STRING and KEGG pathways, to understand the molecular role of each of these genes. Bioinformatics research identified 25 genes and 21 signaling pathways, which allows us to understand pregnancy patients' genetic and biological phenomena and formulate new questions about MS during pregnancy.

Asunto(s)

Biología Computacional , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Femenino , Embarazo , Biología Computacional/métodos , Redes Reguladoras de Genes , Complicaciones del Embarazo/genética , Complicaciones del Embarazo/metabolismo , Perfilación de la Expresión Génica , Transducción de Señal/genética , Regulación de la Expresión Génica

RESUMEN

BACKGROUND: Soybean establishes a mutualistic interaction with nitrogen-fixing rhizobacteria, acquiring most of its nitrogen requirements through symbiotic nitrogen fixation. This crop is susceptible to water deficit; evidence suggests that its nodulation status-whether it is nodulated or not-can influence how it responds to water deficit. The translational control step of gene expression has proven relevant in plants subjected to water deficit. RESULTS: Here, we analyzed soybean roots' differential responses to water deficit at transcriptional, translational, and mixed (transcriptional + translational) levels. Thus, the transcriptome and translatome of four combined-treated soybean roots were analyzed. We found hormone metabolism-related genes among the differentially expressed genes (DEGs) at the translatome level in nodulated and water-restricted plants. Also, weighted gene co-expression network analysis followed by differential expression analysis identified gene modules associated with nodulation and water deficit conditions. Protein-protein interaction network analysis was performed for subsets of mixed DEGs of the modules associated with the plant responses to nodulation, water deficit, or their combination. CONCLUSIONS: Our research reveals that the stand-out processes and pathways in the before-mentioned plant responses partially differ; terms related to glutathione metabolism and hormone signal transduction (2 C protein phosphatases) were associated with the response to water deficit, terms related to transmembrane transport, response to abscisic acid, pigment metabolic process were associated with the response to nodulation plus water deficit. Still, two processes were common: galactose metabolism and branched-chain amino acid catabolism. A comprehensive analysis of these processes could lead to identifying new sources of tolerance to drought in soybean.

Asunto(s)

Glycine max , Raíces de Plantas , Transcriptoma , Glycine max/genética , Glycine max/fisiología , Raíces de Plantas/genética , Raíces de Plantas/metabolismo , Regulación de la Expresión Génica de las Plantas , Nodulación de la Raíz de la Planta/genética , Redes Reguladoras de Genes , Perfilación de la Expresión Génica , Deshidratación

RESUMEN

A long-standing goal of evolutionary biology is to decode how changes in gene regulatory networks contribute to human-specific traits. Human accelerated regions (HARs) are prime candidates for driving gene regulatory modifications in human development. The RBFOX1 locus is densely populated with HARs, providing a set of potential regulatory elements that could have changed its expression in the human lineage. Here, we examined the role of RBFOX1-HARs using transgenic zebrafish reporter assays and identified 15 transcriptional enhancers that are active in the developing nervous system, 9 of which displayed differential activity between the human and chimpanzee sequences. The engineered loss of two selected RBFOX1-HARs in knockout mouse models modified Rbfox1 expression at specific developmental stages and tissues in the brain, influencing the expression and splicing of a high number of Rbfox1 target genes. Our results provided insight into the spatial and temporal changes in gene expression driven by RBFOX1-HARs.

Asunto(s)

Elementos de Facilitación Genéticos , Evolución Molecular , Factores de Empalme de ARN , Animales , Humanos , Ratones , Animales Modificados Genéticamente , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Sitios Genéticos , Ratones Noqueados , Pan troglodytes/genética , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , Pez Cebra/genética

RESUMEN

Glioblastoma (GBM) is the most common form of malignant primary brain tumor with a high mortality rate. The aim of the present study was to investigate the clinical significance of Family with Sequence Similarity 3, Member C, FAM3C, in GBM using bioinformatic-integrated analysis. First, we performed the transcriptomic integration analysis to assess the expression profile of FAM3C in GBM using several data sets (RNA-sequencing and scRNA-sequencing), which were obtained from TCGA and GEO databases. By using the STRING platform, we investigated FAM3C-coregulated genes to construct the protein-protein interaction network. Next, Metascape, Enrichr, and CIBERSORT databases were used. We found FAM3C high expression in GBM with poor survival rates. Further, we observed, via FAM3C coexpression network analysis, that FAM3C plays key roles in several hallmarks of cancer. Surprisingly, we also highlighted five FAM3C­coregulated genes overexpressed in GBM. Specifically, we demonstrated the association between the high expression of FAM3C and the abundance of the different immune cells, which may markedly worsen GBM prognosis. For the first time, our findings suggest that FAM3C not only can be a new emerging biomarker with promising therapeutic values to GBM patients but also gave a new insight into a potential resource for future GBM studies.

Asunto(s)

Biomarcadores de Tumor , Neoplasias Encefálicas , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Mapas de Interacción de Proteínas , Pronóstico , Transcriptoma , Redes Reguladoras de Genes , Biología Computacional/métodos , Tasa de Supervivencia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/biosíntesis , Citocinas

RESUMEN

The absence of detailed knowledge about regulatory interactions makes the use of phenomenological assumptions mandatory in cell biology modeling. Furthermore, the challenges associated with the analysis of these models compel the implementation of mathematical approximations. However, the constraints these methods introduce to biological interpretation are sometimes neglected. Consequently, understanding these restrictions is a very important task for systems biology modeling. In this article, we examine the impact of such simplifications, taking the case of a single-gene autoinhibitory circuit; however, our conclusions are not limited solely to this instance. We demonstrate that models grounded in the same biological assumptions but described at varying levels of detail can lead to different outcomes, that is, different and contradictory phenotypes or behaviors. Indeed, incorporating specific molecular processes like translation and elongation into the model can introduce instabilities and oscillations not seen when these processes are assumed to be instantaneous. Furthermore, incorporating a detailed description of promoter dynamics, usually described by a phenomenological regulatory function, can lead to instability, depending on the cooperative binding mechanism that is acting. Consequently, although the use of a regulating function facilitates model analysis, it may mask relevant aspects of the system's behavior. In particular, we observe that the two cooperative binding mechanisms, both compatible with the same sigmoidal function, can lead to different phenotypes, such as transcriptional oscillations with different oscillation frequencies.

Asunto(s)

Redes Reguladoras de Genes , Modelos Genéticos , Biología de Sistemas/métodos , Regiones Promotoras Genéticas

RESUMEN

In contrast to the hypothesis that aging results from cell-autonomous deterioration processes, the programmed longevity theory proposes that aging arises from a partial inactivation of a "longevity program" aimed at maintaining youthfulness in organisms. Supporting this hypothesis, age-related changes in organisms can be reversed by factors circulating in young blood. Concordantly, the endocrine secretion of exosomal microRNAs (miRNAs) by hypothalamic neural stem cells (htNSCs) regulates the aging rate by enhancing physiological fitness in young animals. However, the specific molecular mechanisms through which hypothalamic-derived miRNAs exert their anti-aging effects remain unexplored. Using experimentally validated miRNA-target gene interactions and single-cell transcriptomic data of brain cells during aging and heterochronic parabiosis, we identify the main pathways controlled by these miRNAs and the cell-type-specific gene networks that are altered due to age-related loss of htNSCs and the subsequent decline in specific miRNA levels in the cerebrospinal fluid (CSF). Our bioinformatics analysis suggests that these miRNAs modulate pathways associated with senescence and cellular stress response, targeting crucial genes such as Cdkn2a, Rps27, and Txnip. The oligodendrocyte lineage appears to be the most responsive to age-dependent loss of exosomal miRNA, leading to significant derepression of several miRNA target genes. Furthermore, heterochronic parabiosis can reverse age-related upregulation of specific miRNA-targeted genes, predominantly in brain endothelial cells, including senescence promoting genes such as Cdkn1a and Btg2. Our findings support the presence of an anti-senescence mechanism triggered by the endocrine secretion of htNSC-derived exosomal miRNAs, which is associated with a youthful transcriptional signature.

Asunto(s)

Envejecimiento , Exosomas , Hipotálamo , MicroARNs , Células-Madre Neurales , MicroARNs/genética , MicroARNs/metabolismo , Animales , Exosomas/metabolismo , Hipotálamo/metabolismo , Envejecimiento/genética , Envejecimiento/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Redes Reguladoras de Genes , Senescencia Celular/genética , Encéfalo/metabolismo , Ratones , Parabiosis , Oligodendroglía/metabolismo , Transcriptoma , Regulación de la Expresión Génica , Perfilación de la Expresión Génica

RESUMEN

In the mouse embryo, the transition from the preimplantation to the postimplantation epiblast is governed by changes in the gene regulatory network (GRN) that lead to transcriptional, epigenetic, and functional changes. This transition can be faithfully recapitulated in vitro by the differentiation of mouse embryonic stem cells (mESCs) to epiblast-like cells (EpiLCs), that reside in naïve and formative states of pluripotency, respectively. However, the GRN that drives this conversion is not fully elucidated. Here we demonstrate that the transcription factor OCT6 is a key driver of this process. Firstly, we show that Oct6 is not expressed in mESCs but is rapidly induced as cells exit the naïve pluripotent state. By deleting Oct6 in mESCs, we find that knockout cells fail to acquire the typical morphological changes associated with the formative state when induced to differentiate. Additionally, the key naïve pluripotency TFs Nanog, Klf2, Nr5a2, Prdm14, and Esrrb were expressed at higher levels than in wild-type cells, indicating an incomplete dismantling of the naïve pluripotency GRN. Conversely, premature expression of Oct6 in naïve cells triggered a rapid morphological transformation mirroring differentiation, that was accompanied by the upregulation of the endogenous Oct6 as well as the formative genes Sox3, Zic2/3, Foxp1, Dnmt3A and FGF5. Strikingly, we found that OCT6 represses Nanog in a bistable manner and that this regulation is at the transcriptional level. Moreover, our findings also reveal that Oct6 is repressed by NANOG. Collectively, our results establish OCT6 as a key TF in the dissolution of the naïve pluripotent state and support a model where Oct6 and Nanog form a double negative feedback loop which could act as an important toggle mediating the transition to the formative state.

Asunto(s)

Diferenciación Celular , Redes Reguladoras de Genes , Células Madre Embrionarias de Ratones , Proteína Homeótica Nanog , Animales , Ratones , Proteína Homeótica Nanog/metabolismo , Proteína Homeótica Nanog/genética , Diferenciación Celular/genética , Células Madre Embrionarias de Ratones/metabolismo , Células Madre Embrionarias de Ratones/citología , Células Madre Pluripotentes/metabolismo , Células Madre Pluripotentes/citología , Regulación del Desarrollo de la Expresión Génica , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Estratos Germinativos/metabolismo , Estratos Germinativos/citología , Ratones Noqueados