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1.
BMC Bioinformatics ; 21(Suppl 14): 359, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32998692

RESUMO

BACKGROUND: The abundance of molecular profiling of breast cancer tissues entailed active research on molecular marker-based early diagnosis of metastasis. Recently there is a surging interest in combining gene expression with gene networks such as protein-protein interaction (PPI) network, gene co-expression (CE) network and pathway information to identify robust and accurate biomarkers for metastasis prediction, reflecting the common belief that cancer is a systems biology disease. However, controversy exists in the literature regarding whether network markers are indeed better features than genes alone for predicting as well as understanding metastasis. We believe much of the existing results may have been biased by the overly complicated prediction algorithms, unfair evaluation, and lack of rigorous statistics. In this study, we propose a simple approach to use network edges as features, based on two types of networks respectively, and compared their prediction power using three classification algorithms and rigorous statistical procedure on one of the largest datasets available. To detect biomarkers that are significant for the prediction and to compare the robustness of different feature types, we propose an unbiased and novel procedure to measure feature importance that eliminates the potential bias from factors such as different sample size, number of features, as well as class distribution. RESULTS: Experimental results reveal that edge-based feature types consistently outperformed gene-based feature type in random forest and logistic regression models under all performance evaluation metrics, while the prediction accuracy of edge-based support vector machine (SVM) model was poorer, due to the larger number of edge features compared to gene features and the lack of feature selection in SVM model. Experimental results also show that edge features are much more robust than gene features and the top biomarkers from edge feature types are statistically more significantly enriched in the biological processes that are well known to be related to breast cancer metastasis. CONCLUSIONS: Overall, this study validates the utility of edge features as biomarkers but also highlights the importance of carefully designed experimental procedures in order to achieve statistically reliable comparison results.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Máquina de Vetores de Suporte , Área Sob a Curva , Neoplasias da Mama/genética , Feminino , Redes Reguladoras de Genes/genética , Humanos , Modelos Logísticos , Metástase Neoplásica , Mapas de Interação de Proteínas/genética , Curva ROC
2.
Nat Commun ; 11(1): 5077, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033240

RESUMO

Although substantial progress has been made in cancer biology and treatment, clinical outcomes of bladder carcinoma (BC) patients are still not satisfactory. The tumor microenvironment (TME) is a potential target. Here, by single-cell RNA sequencing on 8 BC tumor samples and 3 para tumor samples, we identify 19 different cell types in the BC microenvironment, indicating high intra-tumoral heterogeneity. We find that tumor cells down regulated MHC-II molecules, suggesting that the downregulated immunogenicity of cancer cells may contribute to the formation of an immunosuppressive microenvironment. We also find that monocytes undergo M2 polarization in the tumor region and differentiate. Furthermore, the LAMP3 + DC subgroup may be able to recruit regulatory T cells, potentially taking part in the formation of an immunosuppressive TME. Through correlation analysis using public datasets containing over 3000 BC samples, we identify a role for inflammatory cancer-associated fibroblasts (iCAFs) in tumor progression, which is significantly related to poor prognosis. Additionally, we characterize a regulatory network depending on iCAFs. These results could help elucidate the protumor mechanisms of iCAFs. Our results provide deep insight into cancer immunology and provide an essential resource for drug discovery in the future.


Assuntos
Fibroblastos/patologia , Inflamação/patologia , Análise de Sequência de RNA , Análise de Célula Única , Bexiga Urinária/patologia , Área Sob a Curva , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Polaridade Celular , Proliferação de Células , Citocinas/metabolismo , Variações do Número de Cópias de DNA/genética , Células Dendríticas/metabolismo , Redes Reguladoras de Genes , Humanos , Ligantes , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Monócitos/patologia , Células Mieloides/patologia , Proteínas de Neoplasias/metabolismo , Linfócitos T Reguladores/imunologia , Microambiente Tumoral , Bexiga Urinária/imunologia
3.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2357-2360, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018480

RESUMO

In the past decades an extensive mathematical literature was developed to model and analyze gene networks under both deterministic and stochastic formalisms. However, such literature is predominantly focused to deal with the modeling of transcriptional and translational regulation, but results related to post-transcriptional regulation and its connection with transcriptional regulation are poorly investigated. However, it is becoming of paramount importance the need for modeling post-transcriptional regulation via splicing especially for minor organisms or viruses.The aim of this study is to propose a first general basic modeling scheme for modeling gene expression via alternative splicing and investigating the basic deterministic and stochastic features of the pre-mRNA, mRNAs and proteins under different biological conditions.This first study showed the dynamical properties of alternative splicing, the faster kinetics of the pre-mRNA compared to the mRNA and the importance to stochastically model gene networks when considering the post-transcriptional regulation.


Assuntos
Precursores de RNA , Processamento de RNA , Processamento Alternativo , Redes Reguladoras de Genes , Precursores de RNA/metabolismo , Processamento de RNA/genética , RNA Mensageiro/genética
4.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(9): 1053-1060, 2020.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33051418

RESUMO

OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, especially in Asia and Africa. However, the underlying mechanism is still unclear. Consequently, it is important to explore its key genes and prognosis-related genes via bioinformatics. This study aimed to explore the molecular mechanism of HCC by using bioinformatics analysis for HCC gene chip data. METHODS: Microarray data of HCC genes were downloaded from public GEO database and screened for differentially expressed genes (DEGs) by GEO2R analysis. Then DAVID online tool was used for GO annotation and KEGG pathway enrichment analysis. STRING-DB online database and Cytoscape software were used for protein interaction network analysis.GEPIA and Ualcan were applied to evaluate prognosis and promoter methylation level. RESULTS: A total of 87 DEGs of HCC were screened, of which 15 genes were up-regulated and 72 genes were down-regulated. GO annotation indicated that most of the genes were involved in oxidation reduction,cellular amino acid derivative metabolic process, carboxylic acid catabolic process, and response to wounding. KEGG pathways were enriched in linoleic acid metabolism, retinol metabolism, complement and coagulation cascades,steroid hormone biosynthesis, drug metabolism, and other pathways. Two key modules and key genes AURKA and SPP2 were obtained by protein interaction network analysis. Prognostic analysis showed that the 2 genes were significantly correlated with the total survival time of patients with HCC. There was no significant difference in the methylation level of AURKA promoter between the primary tumor group and the normal group (P=0.296) and the methylation level of SPP2 promoter was significantly lower in the primary tumor group than that in the normal group (P<0.001). CONCLUSIONS: HCC-relevant AURKA and SPP2 are obtained via bioinformatics analysis, which are closely related to the prognosis of patients with HCC. Gene promoter methylation is not the main factor for AURKA and SPP2 expression levels.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/genética , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fosfoproteínas
5.
Nat Commun ; 11(1): 5001, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020480

RESUMO

To perform their computational function, genetic circuits change states through a symphony of genetic parts that turn regulator expression on and off. Debugging is frustrated by an inability to characterize parts in the context of the circuit and identify the origins of failures. Here, we take snapshots of a large genetic circuit in different states: RNA-seq is used to visualize circuit function as a changing pattern of RNA polymerase (RNAP) flux along the DNA. Together with ribosome profiling, all 54 genetic parts (promoters, ribozymes, RBSs, terminators) are parameterized and used to inform a mathematical model that can predict circuit performance, dynamics, and robustness. The circuit behaves as designed; however, it is riddled with genetic errors, including cryptic sense/antisense promoters and translation, attenuation, incorrect start codons, and a failed gate. While not impacting the expected Boolean logic, they reduce the prediction accuracy and could lead to failures when the parts are used in other designs. Finally, the cellular power (RNAP and ribosome usage) required to maintain a circuit state is calculated. This work demonstrates the use of a small number of measurements to fully parameterize a regulatory circuit and quantify its impact on host.


Assuntos
RNA Polimerases Dirigidas por DNA/metabolismo , Redes Reguladoras de Genes , Ribossomos/metabolismo , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Modelos Teóricos , Biossíntese de Proteínas , RNA-Seq , Biologia Sintética , Transcrição Genética
6.
Nat Commun ; 11(1): 4928, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004791

RESUMO

High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1, the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1, elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation.


Assuntos
Aclimatação/genética , Cromatina/metabolismo , Grupos Étnicos/genética , Redes Reguladoras de Genes , Modelos Genéticos , Altitude , Doença da Altitude/etnologia , Doença da Altitude/genética , Doença da Altitude/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipóxia Celular/genética , Células Cultivadas , Cromatina/genética , Sequenciamento de Cromatina por Imunoprecipitação , Resistência à Doença/genética , Feminino , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Oxigênio/metabolismo , Polimorfismo de Nucleotídeo Único , Gravidez , Cultura Primária de Células , RNA-Seq , Elementos Reguladores de Transcrição/genética , Seleção Genética , Tibet/etnologia , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Genoma
7.
PLoS Comput Biol ; 16(9): e1008159, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925923

RESUMO

Intracellular spatial heterogeneity is frequently observed in bacteria, where the chromosome occupies part of the cell's volume and a circuit's DNA often localizes within the cell. How this heterogeneity affects core processes and genetic circuits is still poorly understood. In fact, commonly used ordinary differential equation (ODE) models of genetic circuits assume a well-mixed ensemble of molecules and, as such, do not capture spatial aspects. Reaction-diffusion partial differential equation (PDE) models have been only occasionally used since they are difficult to integrate and do not provide mechanistic understanding of the effects of spatial heterogeneity. In this paper, we derive a reduced ODE model that captures spatial effects, yet has the same dimension as commonly used well-mixed models. In particular, the only difference with respect to a well-mixed ODE model is that the association rate constant of binding reactions is multiplied by a coefficient, which we refer to as the binding correction factor (BCF). The BCF depends on the size of interacting molecules and on their location when fixed in space and it is equal to unity in a well-mixed ODE model. The BCF can be used to investigate how spatial heterogeneity affects the behavior of core processes and genetic circuits. Specifically, our reduced model indicates that transcription and its regulation are more effective for genes located at the cell poles than for genes located on the chromosome. The extent of these effects depends on the value of the BCF, which we found to be close to unity. For translation, the value of the BCF is always greater than unity, it increases with mRNA size, and, with biologically relevant parameters, is substantially larger than unity. Our model has broad validity, has the same dimension as a well-mixed model, yet it incorporates spatial heterogeneity. This simple-to-use model can be used to both analyze and design genetic circuits while accounting for spatial intracellular effects.


Assuntos
Bactérias , Redes Reguladoras de Genes/genética , Genes Bacterianos/genética , Modelos Biológicos , Bactérias/química , Bactérias/citologia , Bactérias/genética , Biologia Computacional , Difusão , Espaço Intracelular/química , Espaço Intracelular/genética
8.
PLoS Comput Biol ; 16(9): e1008185, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925942

RESUMO

Cells adjust their metabolism in response to mutations, but how this reprogramming depends on the genetic context is not well known. Specifically, the absence of individual enzymes can affect reprogramming, and thus the impact of mutations in cell growth. Here, we examine this issue with an in silico model of Saccharomyces cerevisiae's metabolism. By quantifying the variability in the growth rate of 10000 different mutant metabolisms that accumulated changes in their reaction fluxes, in the presence, or absence, of a specific enzyme, we distinguish a subset of modifier genes serving as buffers or potentiators of variability. We notice that the most potent modifiers refer to the glycolysis pathway and that, more broadly, they show strong pleiotropy and epistasis. Moreover, the evidence that this subset depends on the specific growing condition strengthens its systemic underpinning, a feature only observed before in a toy model of a gene-regulatory network. Some of these enzymes also modulate the effect that biochemical noise and environmental fluctuations produce in growth. Thus, the reorganization of metabolism induced by mutations has not only direct physiological implications but also transforms the influence that other mutations have on growth. This is a general result with implications in the development of cancer therapies based on metabolic inhibitors.


Assuntos
Redes Reguladoras de Genes/genética , Redes e Vias Metabólicas , Mutação , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Mutação/genética , Mutação/fisiologia , Fenótipo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Biologia de Sistemas
9.
Int J Mol Sci ; 21(19)2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32993015

RESUMO

The outbreak of a novel coronavirus SARS-CoV-2 responsible for the COVID-19 pandemic has caused a worldwide public health emergency. Due to the constantly evolving nature of the coronaviruses, SARS-CoV-2-mediated alterations on post-transcriptional gene regulations across human tissues remain elusive. In this study, we analyzed publicly available genomic datasets to systematically dissect the crosstalk and dysregulation of the human post-transcriptional regulatory networks governed by RNA-binding proteins (RBPs) and micro-RNAs (miRs) due to SARS-CoV-2 infection. We uncovered that 13 out of 29 SARS-CoV-2-encoded proteins directly interacted with 51 human RBPs, of which the majority of them were abundantly expressed in gonadal tissues and immune cells. We further performed a functional analysis of differentially expressed genes in mock-treated versus SARS-CoV-2-infected lung cells that revealed enrichment for the immune response, cytokine-mediated signaling, and metabolism-associated genes. This study also characterized the alternative splicing events in SARS-CoV-2-infected cells compared to the control, demonstrating that skipped exons and mutually exclusive exons were the most abundant events that potentially contributed to differential outcomes in response to the viral infection. A motif enrichment analysis on the RNA genomic sequence of SARS-CoV-2 clearly revealed the enrichment for RBPs such as SRSFs, PCBPs, ELAVs, and HNRNPs, suggesting the sponging of RBPs by the SARS-CoV-2 genome. A similar analysis to study the interactions of miRs with SARS-CoV-2 revealed functionally important miRs that were highly expressed in immune cells, suggesting that these interactions may contribute to the progression of the viral infection and modulate the host immune response across other human tissues. Given the need to understand the interactions of SARS-CoV-2 with key post-transcriptional regulators in the human genome, this study provided a systematic computational analysis to dissect the role of dysregulated post-transcriptional regulatory networks controlled by RBPs and miRs across tissue types during a SARS-CoV-2 infection.


Assuntos
Betacoronavirus/genética , Betacoronavirus/metabolismo , Infecções por Coronavirus/virologia , Redes Reguladoras de Genes , MicroRNAs/genética , Pneumonia Viral/virologia , Processamento Pós-Transcricional do RNA , Proteínas de Ligação a RNA/metabolismo , Regulação da Expressão Gênica , Genoma Viral , Humanos , MicroRNAs/metabolismo , Pandemias , Mapas de Interação de Proteínas , Proteínas de Ligação a RNA/genética
10.
DNA Cell Biol ; 39(10): 1895-1906, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32882141

RESUMO

Acute aortic dissection (AD) is one of the most severe and highly mortality vascular disease. Its actual prevalence may be seriously underestimated. We studied different expression genes to understand gene profile change between acute AD and nondiseased individuals, and then discover potential biomarkers and therapeutic targets of acute AD. In our study, acute AD differentially expressed mRNAs and miRNAs were identified through bioinformatics analysis on Gene Expression Omnibus data sets GSE52093, GSE98770, and GSE92427. Then, comprehensive target prediction and network analysis methods were used to evaluate protein-protein interaction networks and to identify Gene Ontology terms for differentially expressed mRNAs. Differentially expressed mRNAs-miRNAs involved in acute AD were assessed as well. Finally, the quantitative real-time PCR and in vitro experiment was used to validate the results. We found Integral Membrane Protein 2C (ITM2C) was low expressed and miR-107-5p was highly expressed in acute AD tissues. Meanwhile, overexpression miR-107-5p promoted the cell proliferation and inhibited the cell apoptosis in RASMC cells. miR-107-5p inhibited the progression of acute AD through targeted ITM2C.


Assuntos
Aneurisma Dissecante/genética , MicroRNAs/genética , Aneurisma Dissecante/metabolismo , Aneurisma Dissecante/patologia , Animais , Apoptose , Biomarcadores/metabolismo , Proliferação de Células , Células Cultivadas , Redes Reguladoras de Genes , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Miócitos de Músculo Liso/metabolismo , Mapas de Interação de Proteínas , Ratos , Transcriptoma
11.
Ecotoxicol Environ Saf ; 203: 111007, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888586

RESUMO

Soil acidification is one of the crucial global environmental problems, affecting sustainable land use, crop yield, and ecosystem stability. Previous research reported the tolerance of crops to acid soil stress. However, the molecular response of woody plant to acid conditions remains largely unclear. Rhododendron L. is a widely distributed woody plant genus and prefers to grow in acidic soils. Herein, weighted gene coexpression network analysis was performed on R. protistum var. giganteum seedlings subjected to five pH treatments (3.5, 4.5, 5.5, 6.0, 7.0), and their ecophysiological characteristics were determined for the identification of their molecular responses to acidic environments. Through pairwise comparison, 855 differentially expressed genes (DEGs) associated with photosynthesis, cell wall, and phenylpropanoid metabolism were identified. Most of the DEGs related to photosynthesis and cell wall were up-regulated after pH 4.5 treatment. Results implied that the species improves its photosynthetic abilities and changes its cell wall characteristics to adapt to acidic conditions. Weighted gene co-expression network analyses showed that most of the hub genes were annotated to the biosynthetic pathways of ribosomal proteins and photosynthesis. Expression pattern analysis showed that genes encoding subunit ribosomal proteins decreased at pH 7.0 treatment, suggesting that pH 7.0 treatment led to cell injury in the seedlings. The species regulates protein synthesis in response to high pH stress (pH 7.0). The present study revealed the molecular response mechanism of woody plant R. protistum var. giganteum to acid environments. These findings can be useful in enriching current knowledge of how woody species adapt to soil acidification under global environmental changes.


Assuntos
Ácidos/farmacologia , Parede Celular/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Madeira/efeitos dos fármacos , Parede Celular/genética , Parede Celular/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Fotossíntese/genética , Plântula/efeitos dos fármacos , Plântula/metabolismo , Solo/química , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Madeira/genética , Madeira/metabolismo
12.
Int J Mol Med ; 46(4): 1266-1273, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32945352

RESUMO

The outbreak of the 2019 coronavirus disease (named, COVID­19), caused by the novel SARS­CoV­2 virus, represents a worldwide severe threat to public health. It is of the utmost importance to characterize the immune responses against the SARS­CoV­2 and the mechanisms of hyperinflammation, in order to design better therapeutic strategies for COVID­19. In the present study, a transcriptomic analysis was performed to profile the immune signatures in lung and the bronchoalveolar lavage fluid samples from COVID­19 patients and controls. Our data concordantly revealed increased humoral responses to infection. The elucidation of the host responses to SARS­CoV­2 infection may further improve our understanding of COVID­19 pathogenesis and suggest better therapeutic strategies.


Assuntos
Linfócitos B/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Ativação Linfocitária , Pneumonia Viral/imunologia , Transcriptoma , Linfócitos B/metabolismo , Betacoronavirus/fisiologia , Líquido da Lavagem Broncoalveolar , Infecções por Coronavirus/genética , Bases de Dados Factuais , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Pandemias , Pneumonia Viral/genética
13.
Nat Commun ; 11(1): 4440, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895374

RESUMO

Traditionally engineered genetic circuits have almost exclusively used naturally occurring transcriptional repressors. Recently, non-natural transcription factors (repressors) have been engineered and employed in synthetic biology with great success. However, transcriptional anti-repressors have largely been absent with regard to the regulation of genes in engineered genetic circuits. Here, we present a workflow for engineering systems of non-natural anti-repressors. In this study, we create 41 inducible anti-repressors. This collection of transcription factors respond to two distinct ligands, fructose (anti-FruR) or D-ribose (anti-RbsR); and were complemented by 14 additional engineered anti-repressors that respond to the ligand isopropyl ß-d-1-thiogalactopyranoside (anti-LacI). In turn, we use this collection of anti-repressors and complementary genetic architectures to confer logical control over gene expression. Here, we achieved all NOT oriented logical controls (i.e., NOT, NOR, NAND, and XNOR). The engineered transcription factors and corresponding series, parallel, and series-parallel genetic architectures represent a nascent anti-repressor based transcriptional programming structure.


Assuntos
Bioengenharia/métodos , Repressores Lac/antagonistas & inibidores , Proteínas de Escherichia coli/metabolismo , Expressão Gênica/fisiologia , Redes Reguladoras de Genes , Repressores Lac/síntese química , Ligantes , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/síntese química , Biologia Sintética/métodos , Fatores de Transcrição/síntese química , Fatores de Transcrição/metabolismo
14.
Medicine (Baltimore) ; 99(36): e21653, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32898999

RESUMO

The expression profile and specific roles of microRNAs (miRNAs) in regulation of atrophic bone nonunion are not fully understood. Here, we present evidence that miRNAs are involved in regulation of several osteogenic genes and may contribute to the development of atrophic bone nonunion.The miRNA expression profile of repairing tissues in atrophic bone nonunion patients (group A) and in callus tissues from patients with healed fractures (group B) were quantitatively measured. microRNA microarrays were used to identify differentially expressed miRNAs, and the bioinformatics methods were used to predict the potential target genes. Quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and dual-luciferase reporter assay were performed in human bone marrow stromal cells (hBMSCs) to validate the microarray results.Nine miRNAs in group A were up-regulated 1.5 times compared to group B, while the other 9 miRNAs in group A were down-regulated 1.5 times. Several target regions of these miRNAs were identified in the osteogenic genes, as well as in the other genes in their families or related regulatory factors. Four miRNAs (hsa-miR-149, hsa-miR-221, hsa-miR-628-3p, and hsa-miR-654-5p) could play important roles in regulating bone nonunion development. hBMSCs transfected with these miRNAs significantly decreased mRNA levels of alkaline phosphatase, liver/bone/kidney (ALPL), platelet derived growth factor subunit A (PDGFA), and bone morphogenetic protein 2 (BMP2). Lower protein expression levels were observed using western blotting, confirming that ALPL, PDGFA, and BMP2 were directly targeted by hsa-miR-149, hsa-miR-221, and hsa-miR-654-5p, respectively.In summary, hsa-miR-149, hsa-miR-221, and hsa-miR-654-5p may play important biological roles by repressing osteogenic target genes ALPL, PDGFA, and BMP2, and, therefore, contributing to progression of atrophic bone nonunion.


Assuntos
Osso e Ossos/metabolismo , Fraturas do Fêmur/genética , Fraturas do Úmero/genética , MicroRNAs/metabolismo , Fraturas da Tíbia/genética , Adulto , Criança , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Regulação para Cima
15.
BMC Bioinformatics ; 21(1): 396, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894041

RESUMO

BACKGROUND: MicroRNAs are a class of important small noncoding RNAs, which have been reported to be involved in the processes of tumorigenesis and development by targeting a few genes. Existing studies show that the imbalance between cell proliferation and apoptosis is closely related to the initiation and development of cancers. However, the impact of miRNAs on this imbalance has not been studied systematically. RESULTS: In this study, we first construct a cell fate miRNA-gene regulatory network. Then, we propose a systematical method for calculating the global impact of miRNAs on cell fate genes based on the shortest path. Results on breast cancer and liver cancer datasets show that most of the cell fate genes are perturbed by the differentially expressed miRNAs. Most of the top-identified miRNAs are verified in the Human MicroRNA Disease Database (HMDD) and are related to breast and liver cancers. Function analysis shows that the top 20 miRNAs regulate multiple cell fate related function modules and interact tightly based on their functional similarity. Furthermore, more than half of them can promote sensitivity or induce resistance to some anti-cancer drugs. Besides, survival analysis demonstrates that the top-ranked miRNAs are significantly related to the overall survival time in the breast and liver cancers group. CONCLUSION: In sum, this study can help to systematically study the important role of miRNAs on proliferation and apoptosis and thereby uncover the key miRNAs during the process of tumorigenesis. Furthermore, the results of this study will contribute to the development of clinical therapy based miRNAs for cancers.


Assuntos
Apoptose/genética , Proliferação de Células/genética , MicroRNAs/metabolismo , Biomarcadores/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Bases de Dados Genéticas , Feminino , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , MicroRNAs/genética , RNA Mensageiro/metabolismo , Análise de Sobrevida
17.
BMC Bioinformatics ; 21(Suppl 8): 199, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938402

RESUMO

BACKGROUND: Non-coding RNAs include different classes of molecules with regulatory functions. The most studied are microRNAs (miRNAs) that act directly inhibiting mRNA expression or protein translation through the interaction with a miRNAs-response element. Other RNA molecules participate in the complex network of gene regulation. They behave as competitive endogenous RNA (ceRNA), acting as natural miRNA sponges to inhibit miRNA functions and modulate the expression of RNA messenger (mRNA). It became evident that understanding the ceRNA-miRNA-mRNA crosstalk would increase the functional information across the transcriptome, contributing to identify new potential biomarkers for translational medicine. RESULTS: We present miRTissue ce, an improvement of our original miRTissue web service. By introducing a novel computational pipeline, miRTissue ce provides an easy way to search for ceRNA interactions in several cancer tissue types. Moreover it extends the functionalities of previous miRTissue release about miRNA-target interaction in order to provide a complete insight about miRNA mediated regulation processes. miRTissue ce is freely available at http://tblab.pa.icar.cnr.it/mirtissue.html . CONCLUSIONS: The study of ceRNA networks and its dynamics in cancer tissue could be applied in many fields of translational biology, as the investigation of new cancer biomarker, both diagnostic and prognostic, and also in the investigation of new therapeutic strategies of intervention. In this scenario, miRTissue ce can offer a powerful instrument for the analysis and characterization of ceRNA-ceRNA interactions in different tissue types, representing a fundamental step in order to understand more complex regulation mechanisms.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , MicroRNAs/genética , RNA Neoplásico/genética , Humanos , Prognóstico
18.
Nat Commun ; 11(1): 4873, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978376

RESUMO

Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous neurodevelopmental disorder. Despite this heterogeneity, previous studies have shown patterns of molecular convergence in post-mortem brain tissue from autistic subjects. Here, we integrate genome-wide measures of mRNA expression, miRNA expression, DNA methylation, and histone acetylation from ASD and control brains to identify a convergent molecular subtype of ASD with shared dysregulation across both the epigenome and transcriptome. Focusing on this convergent subtype, we substantially expand the repertoire of differentially expressed genes in ASD and identify a component of upregulated immune processes that are associated with hypomethylation. We utilize eQTL and chromosome conformation datasets to link differentially acetylated regions with their cognate genes and identify an enrichment of ASD genetic risk variants in hyperacetylated noncoding regulatory regions linked to neuronal genes. These findings help elucidate how diverse genetic risk factors converge onto specific molecular processes in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Epigenômica/métodos , RNA Mensageiro/metabolismo , Transcriptoma , Encéfalo/metabolismo , Metilação de DNA , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Genômica , Histonas/metabolismo , Humanos , MicroRNAs
19.
Medicine (Baltimore) ; 99(39): e22105, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991406

RESUMO

BACKGROUND: Lymph node metastasis is a significant problem in breast cancer, and its underlying molecular mechanism is still unclear. The purpose of this study is to research the molecular mechanism and to explore the key RNAs and pathways that mediate lymph node metastasis in breast cancer. METHODS: GSE100453 and GSE38167 were downloaded from the Gene Expression Omnibus (GEO) database and 569 breast cancer statistics were also downloaded from the TCGA database. Differentially expressed miRNAs were calculated by using R software and GEO2R. Gene ontology and Enriched pathway analysis of target mRNAs were analyzed by using the Database for Database of Annotation Visualization and Integrated Discovery (DAVID) and R software. The protein-protein interaction (PPI) network was performed according to Metascape, String, and Cytoscape software. RESULTS: In total, 6 differentially expressed miRNAs were selected, and 499 mRNAs were identified after filtering. The research of the Kyoto Encyclopedia of Genes and Genomes (KEGG) demonstrated that mRNAs enriched in certain tumor pathways. Also, certain hub mRNAs were highlighted after constructed and analyzed the PPI network. A total of 3 out of 6 miRNAs had a significant relationship with the overall survival (P < .05) and showed a good ability of risk prediction model of over survival. CONCLUSIONS: By utilizing bioinformatics analyses, differently expressed miRNAs were identified and constructed a complete gene network. Several potential mechanisms and therapeutic and prognostic targets of lymph node metastasis were also demonstrated in breast cancer.


Assuntos
Neoplasias da Mama/genética , Metástase Linfática/genética , Biologia Computacional , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Mapas de Interação de Proteínas , Microambiente Tumoral
20.
PLoS One ; 15(8): e0238256, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866176

RESUMO

In recent years, the binary definition of sex is being challenged by repetitive reports about individuals with ambiguous sexual identity from various animal groups. This has created an urge to decode the molecular mechanism underlying sexual development. However, sexual ambiguities are extremely uncommon in nature, limiting their experimental value. Here, we report the establishment of a genetically modified clone of Daphnia magna from which intersex daphniids can be readily generated. By mutating the conserved central sex determining factor Doublesex1, body-wide feminization of male daphniid could be achieved. Comparative transcriptomic analysis also revealed a genetic network correlated with Doublesex1 activity which may account for the establishment of sexual identity in D. magna. We found that Dsx1 repressed genes related to growth and promoted genes related to signaling. We infer that different intersex phenotypes are the results of fluctuation in activity of these Dsx1 downstream factors. Our results demonstrated that the D. magna genome is capable of expressing sex in a continuous array, supporting the idea that sex is actually a spectrum.


Assuntos
Daphnia/genética , Daphnia/fisiologia , Transtornos do Desenvolvimento Sexual/genética , Redes Reguladoras de Genes/genética , Desenvolvimento Sexual/genética , Sequência de Aminoácidos , Animais , Genoma/genética , Fenótipo , Transcriptoma/genética
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