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1.
BMC Bioinformatics ; 21(Suppl 14): 368, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32998690

RESUMO

BACKGROUND: Lung cancer is the leading cause of the largest number of deaths worldwide and lung adenocarcinoma is the most common form of lung cancer. In order to understand the molecular basis of lung adenocarcinoma, integrative analysis have been performed by using genomics, transcriptomics, epigenomics, proteomics and clinical data. Besides, molecular prognostic signatures have been generated for lung adenocarcinoma by using gene expression levels in tumor samples. However, we need signatures including different types of molecular data, even cohort or patient-based biomarkers which are the candidates of molecular targeting. RESULTS: We built an R pipeline to carry out an integrated meta-analysis of the genomic alterations including single-nucleotide variations and the copy number variations, transcriptomics variations through RNA-seq and clinical data of patients with lung adenocarcinoma in The Cancer Genome Atlas project. We integrated significant genes including single-nucleotide variations or the copy number variations, differentially expressed genes and those in active subnetworks to construct a prognosis signature. Cox proportional hazards model with Lasso penalty and LOOCV was used to identify best gene signature among different gene categories. We determined a 12-gene signature (BCHE, CCNA1, CYP24A1, DEPTOR, MASP2, MGLL, MYO1A, PODXL2, RAPGEF3, SGK2, TNNI2, ZBTB16) for prognostic risk prediction based on overall survival time of the patients with lung adenocarcinoma. The patients in both training and test data were clustered into high-risk and low-risk groups by using risk scores of the patients calculated based on selected gene signature. The overall survival probability of these risk groups was highly significantly different for both training and test datasets. CONCLUSIONS: This 12-gene signature could predict the prognostic risk of the patients with lung adenocarcinoma in TCGA and they are potential predictors for the survival-based risk clustering of the patients with lung adenocarcinoma. These genes can be used to cluster patients based on molecular nature and the best candidates of drugs for the patient clusters can be proposed. These genes also have a high potential for targeted cancer therapy of patients with lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/patologia , Genômica/métodos , Neoplasias Pulmonares/patologia , Transcriptoma , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Área Sob a Curva , Análise por Conglomerados , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Mapas de Interação de Proteínas/genética , Curva ROC , Fatores de Risco , Taxa de Sobrevida
2.
Nat Commun ; 11(1): 4939, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009390

RESUMO

Acoustic communication is enabled by the evolution of specialised hearing and sound producing organs. In this study, we performed a large-scale macroevolutionary study to understand how both hearing and sound production evolved and affected diversification in the insect order Orthoptera, which includes many familiar singing insects, such as crickets, katydids, and grasshoppers. Using phylogenomic data, we firmly establish phylogenetic relationships among the major lineages and divergence time estimates within Orthoptera, as well as the lineage-specific and dynamic patterns of evolution for hearing and sound producing organs. In the suborder Ensifera, we infer that forewing-based stridulation and tibial tympanal ears co-evolved, but in the suborder Caelifera, abdominal tympanal ears first evolved in a non-sexual context, and later co-opted for sexual signalling when sound producing organs evolved. However, we find little evidence that the evolution of hearing and sound producing organs increased diversification rates in those lineages with known acoustic communication.


Assuntos
Acústica , Evolução Biológica , Gafanhotos/classificação , Gafanhotos/genética , Filogenia , Vocalização Animal , Animais , Teorema de Bayes , Genoma Mitocondrial , Gafanhotos/anatomia & histologia , Audição/fisiologia , Modelos Biológicos , Som , Fatores de Tempo , Transcriptoma/genética
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1585-1591, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067958

RESUMO

OBJECTIVE: To identify the molecular pathogenesis of diffuse large B cell lymphoma (DLBCL) and to screen potential biomarkers or therapeutic targets for diagnosis, treatment and prognosis evaluation of patients with DLBCL. METHODS: Gene expression profiles of GSE56315 were downloaded from GEO database. Analysis of differentially expressed genes (DEGs) in the microarray was performed using"R"software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of up-regulated DEGs were performed using DAVID database. The survival analysis of up-regulated DEGs was performed using GEPIA database. RESULTS: There were 55 DLBCL biopsy tissue specimes and 33 normal tonsil tissue specimes in the datasets. A total of 2001 differentially expressed genes were identified, including 1 079 up-regulated DEGs and 922 down-regulated DEGs. Function enrichment analysis indicated that the up-regulated DEGs were involved in 425 GO terms, including 31 genes of FDR<0.05 (P<0.05) and 17 pathways. In the GEPIA database, the expression levels of 12 up-regulated DEGs (AK8、AP2M1、ATOX1、 CSF2RA、CYP27A1、HEBP1、HTRA1、HTRA4、IGFBP3、PTGDS、SIGLEC15、UQCRC1) were found to be significantly correlated with shorter overall survival of DLBCL patients. CONCLUSION: The internal biological information in DLBCL revealed by integrative bioinformatical analysis may provide an important theoretical basis for further research on molecular mechanism of DLBCL, screening of potential therapeutic targets and evaluation of prognosis.


Assuntos
Biologia Computacional , Linfoma Difuso de Grandes Células B , Perfilação da Expressão Gênica , Ontologia Genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Linfoma Difuso de Grandes Células B/genética , Transcriptoma
4.
Nat Commun ; 11(1): 4956, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009383

RESUMO

Tet-enzyme-mediated 5-hydroxymethylation of cytosines in DNA plays a crucial role in mouse embryonic stem cells (ESCs). In RNA also, 5-hydroxymethylcytosine (5hmC) has recently been evidenced, but its physiological roles are still largely unknown. Here we show the contribution and function of this mark in mouse ESCs and differentiating embryoid bodies. Transcriptome-wide mapping in ESCs reveals hundreds of messenger RNAs marked by 5hmC at sites characterized by a defined unique consensus sequence and particular features. During differentiation a large number of transcripts, including many encoding key pluripotency-related factors (such as Eed and Jarid2), show decreased cytosine hydroxymethylation. Using Tet-knockout ESCs, we find Tet enzymes to be partly responsible for deposition of 5hmC in mRNA. A transcriptome-wide search further reveals mRNA targets to which Tet1 and Tet2 bind, at sites showing a topology similar to that of 5hmC sites. Tet-mediated RNA hydroxymethylation is found to reduce the stability of crucial pluripotency-promoting transcripts. We propose that RNA cytosine 5-hydroxymethylation by Tets is a mark of transcriptome flexibility, inextricably linked to the balance between pluripotency and lineage commitment.


Assuntos
5-Metilcitosina/análogos & derivados , Diferenciação Celular , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , RNA/metabolismo , 5-Metilcitosina/metabolismo , Animais , Especificidade de Anticorpos/imunologia , Sequência de Bases , Corpos Embrioides/metabolismo , Camundongos , Modelos Biológicos , Células-Tronco Pluripotentes/metabolismo , Ligação Proteica , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma/genética
5.
Mol Cell ; 80(1): 156-163.e6, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007255

RESUMO

The production of alternative RNA variants contributes to the tissue-specific regulation of gene expression. In the animal nervous system, a systematic shift toward distal sites of transcription termination produces transcript signatures that are crucial for neuron development and function. Here, we report that, in Drosophila, the highly conserved protein ELAV globally regulates all sites of neuronal 3' end processing and directly binds to proximal polyadenylation sites of target mRNAs in vivo. We uncover an endogenous strategy of functional gene rescue that safeguards neuronal RNA signatures in an ELAV loss-of-function context. When not directly repressed by ELAV, the transcript encoding the ELAV paralog FNE acquires a mini-exon, generating a new protein able to translocate to the nucleus and rescue ELAV-mediated alternative polyadenylation and alternative splicing. We propose that exon-activated functional rescue is a more widespread mechanism that ensures robustness of processes regulated by a hierarchy, rather than redundancy, of effectors.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Proteínas ELAV/metabolismo , Éxons/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Masculino , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma/genética
6.
Front Immunol ; 11: 2063, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013872

RESUMO

Background: Cases of excessive neutrophil counts in the blood in severe coronavirus disease (COVID-19) patients have drawn significant attention. Neutrophil infiltration was also noted on the pathological findings from autopsies. It is urgent to clarify the pathogenesis of neutrophils leading to severe pneumonia in COVID-19. Methods: A retrospective analysis was performed on 55 COVID-19 patients classified as mild (n = 22), moderate (n = 25), and severe (n = 8) according to the Guidelines released by the National Health Commission of China. Trends relating leukocyte counts and lungs examined by chest CT scan were quantified by Bayesian inference. Transcriptional signatures of host immune cells of four COVID19 patients were analyzed by RNA sequencing of lung specimens and BALF. Results: Neutrophilia occurred in 6 of 8 severe patients at 7-19 days after symptom onset, coinciding with lesion progression. Increasing neutrophil counts paralleled lesion CT values (slope: 0.8 and 0.3-1.2), reflecting neutrophilia-induced lung injury in severe patients. Transcriptome analysis revealed that neutrophil activation was correlated with 17 neutrophil extracellular trap (NET)-associated genes in COVID-19 patients, which was related to innate immunity and interacted with T/NK/B cells, as supported by a protein-protein interaction network analysis. Conclusion: Excessive neutrophils and associated NETs could explain the pathogenesis of lung injury in COVID-19 pneumonia.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/imunologia , Armadilhas Extracelulares/genética , Ativação de Neutrófilo/genética , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Teorema de Bayes , Infecções por Coronavirus/virologia , Feminino , Humanos , Contagem de Leucócitos , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Masculino , Pessoa de Meia-Idade , Infiltração de Neutrófilos/imunologia , Pandemias , Pneumonia Viral/virologia , Mapas de Interação de Proteínas/imunologia , RNA Viral/genética , Estudos Retrospectivos , Transcriptoma
7.
Sci Data ; 7(1): 334, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037224

RESUMO

Plant growth and development are regulated by a tightly controlled interplay between cell division, cell expansion and cell differentiation during the entire plant life cycle from seed germination to maturity and seed propagation. To explore some of the underlying molecular mechanisms in more detail, we selected different aerial tissue types of the model plant Arabidopsis thaliana, namely rosette leaf, flower and silique/seed and performed proteomic, phosphoproteomic and transcriptomic analyses of sequential growth stages using tandem mass tag-based mass spectrometry and RNA sequencing. With this exploratory multi-omics dataset, development dynamics of photosynthetic tissues can be investigated from different angles. As expected, we found progressive global expression changes between growth stages for all three omics types and often but not always corresponding expression patterns for individual genes on transcript, protein and phosphorylation site level. The biggest difference between proteomic- and transcriptomic-based expression information could be observed for seed samples. Proteomic and transcriptomic data is available via ProteomeXchange and ArrayExpress with the respective identifiers PXD018814 and E-MTAB-7978.


Assuntos
Arabidopsis , Proteoma , Arabidopsis/genética , Perfilação da Expressão Gênica , Proteoma/genética , Proteômica , Transcriptoma
8.
Medicine (Baltimore) ; 99(35): e21895, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871920

RESUMO

MicroRNAs (miRNAs) refers to a small, short non-coding RNA of endogenous class. They have shown to have an increasingly altered expression in many types of cancer, including colorectal cancer (CRC).In the present study, miRNA TaqManMGB and qRT-PCR was used to quantify the expression and clinical significance of 3 mature human miRNA in 82 pairs of colorectal adenocarcinoma tissues and normal adjacent tissue samples (NATS) collected from patients of the south-east part of Romania. Differences between CRC and NATS were analyzed using Wilcoxon test, while correlations between miRNAs expression levels and clinicopathological features were examined using non-parametric tests. In addition, the ability of selected miRNAs to function as biomarkers and, as potential indicators in CRC prognosis was also examined.When the miRNA expression was compared in CRC related NATS, miR-143, and miR-145 were significantly underexpressed (4.99 ±â€Š-1.02 vs -5.66 ±â€Š-1.66, P < .001; -4.85 ±â€Š-0.59 vs -9.27 ±â€Š-1.51, P < .001, respectively), while the pattern of miR-92a was significantly overexpressed (-5.55 ±â€Š-2.83 vs -4.92 ±â€Š-2.44, P < .001). Moreover, the expression levels of selected miRNAs were identified to be correlated with gradual increases in fold change expression with the depth of tumor invasion, lymph node invasion, and maximal increases with distant metastasis. Furthermore, the receiver operating characteristic analysis demonstrated that potential diagnostic of miR-143, miR-145, and miR-92a in discriminating CRC from NATS, with the area under the curve of 0.74, 0.85, and 0.84 respectively. The Kaplan-Meier and the log-rank test showed that a high level of miR-92a and low levels of miR-143 and miR-145 predicted poor survival rate in our cohorts.In conclusion, we can summarize that miR-145 and miR-143 are decreased, while miR-92 is increased in CRC compared to NATS, and associated with different stages of CRC pathogenesis. Thus, the expression of selected miRNAs can represent potential diagnostic and prognostic tools in patients with CRC from Romania.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , MicroRNAs/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Área Sob a Curva , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Romênia , Transcriptoma
9.
Medicine (Baltimore) ; 99(35): e21997, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871953

RESUMO

BACKGROUND: Ulcerative colitis (UC) was a type of inflammatory bowel diseases, which was difficult to cure and even would malignant turn into colon cancer. The specific etiology and molecular mechanism of UC were unclear to date. The purpose of this study was to search for new targets for the diagnosis and treatment of UC. METHODS: Firstly, we downloaded the gene expression data of UC from the gene expression omnibus database database (GSE107499), and used multiple bioinformatics methods to find differently expressed genes (DEGs) in UC. Subsequently, we evaluated the lymphocyte infiltration in UC inflamed colon tissue by using the cell type identification by estimating relative subset of known RNA transcripts method. RESULTS: We obtained 1175 DEGs and 8 hub genes (IL6, TNF, PTPRC, CXCL8, FN1, CD44, IL1B, and MMP9) in this study. Among them, 903 DEGs were up-regulated and 272 DEGs were down-regulated. Compared with non-inflamed colon tissues, the inflamed colon tissues had higher levels of memory B cells, activated memory CD4 T cells, follicular helper T cells, M1 macrophages, resting dendritic cells, activated dendritic cells, activated mast cells, and neutrophils, whereas the proportions of plasma cells, resting memory CD4 T cells, gamma delta T cells, activated NK cells, M2 macrophages and resting mast cells were relatively lower. CONCLUSIONS: The DEGs, hub genes and different lymphatic infiltration conditions can provide new targets for diagnosis and treatment of UC. However, these were just predictions through some theoretical methods, and more basic experiments will be needed to prove in the future.


Assuntos
Colite Ulcerativa/metabolismo , Linfócitos/fisiologia , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Biologia Computacional , Humanos , Mapas de Interação de Proteínas , Transcriptoma
10.
Medicine (Baltimore) ; 99(35): e22047, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871963

RESUMO

BACKGROUND: We identified the hub genes and pathways dysregulated in acute myeloid leukemia and the potential molecular mechanisms involved. METHODS: We downloaded the GSE15061 gene expression dataset from the Gene Expression Omnibus database and used weighted gene co-expression network analysis to identify hub genes. Differential expression of the genes was evaluated using the limma package in R software. Subsequently, we built a protein-protein interaction network followed by functional enrichment analysis. Then, the prognostic significance of gene expression was explored in terms of overall survival. Finally, transcription factor-mRNA (ribonucleic acid) and microRNA-mRNA interaction analysis was also explored. RESULTS: We identified 100 differentially expressed hub genes. Functional enrichment analysis indicated that the genes were principally involved in immune system regulation, host defense, and negative regulation of apoptosis and myeloid cell differentiation. We identified 4 hub genes, the expression of which was significantly correlated with overall survival. Finally, 26 key regulators for hub genes and 38 microRNA-mRNA interactions were identified. CONCLUSION: We performed a comprehensive bioinformatics analysis of hub genes potentially involved in acute myeloid leukemia development. Further molecular biological experiments are required to confirm the roles played by these genes.


Assuntos
Leucemia Mieloide Aguda/metabolismo , Biologia Computacional , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , MicroRNAs/metabolismo , Mapas de Interação de Proteínas , Análise de Sobrevida , Fatores de Transcrição/metabolismo , Transcriptoma
11.
Nat Commun ; 11(1): 4365, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868761

RESUMO

Current approaches explore bacterial genes that change transcriptionally upon stress exposure as diagnostics to predict antibiotic sensitivity. However, transcriptional changes are often specific to a species or antibiotic, limiting implementation to known settings only. While a generalizable approach, predicting bacterial fitness independent of strain, species or type of stress, would eliminate such limitations, it is unclear whether a stress-response can be universally captured. By generating a multi-stress and species RNA-Seq and experimental evolution dataset, we highlight the strengths and limitations of existing gene-panel based methods. Subsequently, we build a generalizable method around the observation that global transcriptional disorder seems to be a common, low-fitness, stress response. We quantify this disorder using entropy, which is a specific measure of randomness, and find that in low fitness cases increasing entropy and transcriptional disorder results from a loss of regulatory gene-dependencies. Using entropy as a single feature, we show that fitness and quantitative antibiotic sensitivity predictions can be made that generalize well beyond training data. Furthermore, we validate entropy-based predictions in 7 species under antibiotic and non-antibiotic conditions. By demonstrating the feasibility of universal predictions of bacterial fitness, this work establishes the fundamentals for potentially new approaches in infectious disease diagnostics.


Assuntos
Bactérias/genética , Evolução Molecular Direcionada , Farmacorresistência Bacteriana/genética , Estresse Fisiológico , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/metabolismo , Fenômenos Fisiológicos Bacterianos , Doenças Transmissíveis/diagnóstico , Entropia , Regulação Bacteriana da Expressão Gênica , Genes Bacterianos , Genoma Bacteriano , Análise de Sequência de RNA , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/metabolismo , Transcriptoma
12.
Proc Biol Sci ; 287(1934): 20200875, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32900318

RESUMO

Recently diverged taxa with contrasting phenotypes offer opportunities for unravelling the genetic basis of phenotypic variation in nature. Horseshoe bats are a speciose group that exhibit a derived form of high-duty cycle echolocation in which the inner ear is finely tuned to echoes of the narrowband call frequency. Here, by focusing on three recently diverged subspecies of the intermediate horseshoe bat (Rhinolophus affinis) that display divergent echolocation call frequencies, we aim to identify candidate loci putatively involved in hearing frequency variation. We used de novo transcriptome sequencing of two mainland taxa (himalayanus and macrurus) and one island taxon (hainanus) to compare expression profiles of thousands of genes. By comparing taxa with divergent call frequencies (around 15 kHz difference), we identified 252 differentially expressed genes, of which six have been shown to be involved in hearing or deafness in human/mouse. To obtain further validation of these results, we applied quantitative reverse transcription-PCR to the candidate gene FBXL15 and found a broad association between the level of expression and call frequency across taxa. The genes identified here represent strong candidate loci associated with hearing frequency variation in bats.


Assuntos
Quirópteros/genética , Ecolocação/fisiologia , Transcriptoma , Animais , Fluxo Gênico , Audição , Filogenia
13.
Nat Commun ; 11(1): 4678, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938916

RESUMO

Diabetic foot ulcers (DFUs) are a life-threatening disease that often result in lower limb amputations and a shortened lifespan. However, molecular mechanisms contributing to the pathogenesis of DFUs remain poorly understood. We use next-generation sequencing to generate a human dataset of pathogenic DFUs to compare to transcriptional profiles of human skin and oral acute wounds, oral as a model of "ideal" adult tissue repair due to accelerated closure without scarring. Here we identify major transcriptional networks deregulated in DFUs that result in decreased neutrophils and macrophages recruitment and overall poorly controlled inflammatory response. Transcription factors FOXM1 and STAT3, which function to activate and promote survival of immune cells, are inhibited in DFUs. Moreover, inhibition of FOXM1 in diabetic mouse models (STZ-induced and db/db) results in delayed wound healing and decreased neutrophil and macrophage recruitment in diabetic wounds in vivo. Our data underscore the role of a perturbed, ineffective inflammatory response as a major contributor to the pathogenesis of DFUs, which is facilitated by FOXM1-mediated deregulation of recruitment of neutrophils and macrophages, revealing a potential therapeutic strategy.


Assuntos
Pé Diabético/genética , Pé Diabético/imunologia , Proteína Forkhead Box M1/imunologia , Cicatrização/imunologia , Adulto , Idoso , Animais , Proliferação de Células , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/imunologia , Pé Diabético/patologia , Modelos Animais de Doenças , Feminino , Proteína Forkhead Box M1/antagonistas & inibidores , Proteína Forkhead Box M1/metabolismo , Humanos , Inflamação/genética , Inflamação/imunologia , Masculino , Camundongos Endogâmicos , Pessoa de Meia-Idade , Mucosa Bucal/fisiologia , Piridinas/farmacologia , Tiofenos/farmacologia , Transcriptoma/fisiologia , Cicatrização/genética
14.
Sci Data ; 7(1): 314, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963239

RESUMO

Establishing consensus around the transcriptional interface between coronavirus (CoV) infection and human cellular signaling pathways can catalyze the development of novel anti-CoV therapeutics. Here, we used publicly archived transcriptomic datasets to compute consensus regulatory signatures, or consensomes, that rank human genes based on their rates of differential expression in MERS-CoV (MERS), SARS-CoV-1 (SARS1) and SARS-CoV-2 (SARS2)-infected cells. Validating the CoV consensomes, we show that high confidence transcriptional targets (HCTs) of MERS, SARS1 and SARS2 infection intersect with HCTs of signaling pathway nodes with known roles in CoV infection. Among a series of novel use cases, we gather evidence for hypotheses that SARS2 infection efficiently represses E2F family HCTs encoding key drivers of DNA replication and the cell cycle; that progesterone receptor signaling antagonizes SARS2-induced inflammatory signaling in the airway epithelium; and that SARS2 HCTs are enriched for genes involved in epithelial to mesenchymal transition. The CoV infection consensomes and HCT intersection analyses are freely accessible through the Signaling Pathways Project knowledgebase, and as Cytoscape-style networks in the Network Data Exchange repository.


Assuntos
Infecções por Coronavirus/genética , Transição Epitelial-Mesenquimal/genética , Pneumonia Viral/genética , Transcriptoma , Betacoronavirus , Ciclo Celular , Consenso , Replicação do DNA , Conjuntos de Dados como Assunto , Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Coronavírus da Síndrome Respiratória do Oriente Médio , Pandemias , Receptores de Progesterona , Vírus da SARS , Transdução de Sinais
15.
Nat Commun ; 11(1): 4788, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963234

RESUMO

Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes.


Assuntos
Proliferação de Células , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Animais , Diferenciação Celular , Modelos Animais de Doenças , Epiderme/metabolismo , Epiderme/patologia , GTP Fosfo-Hidrolases , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Hiperplasia/patologia , Queratinócitos/patologia , Camundongos , Camundongos Knockout , Membrana Mucosa/metabolismo , Prognóstico , RNA Mensageiro/metabolismo , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Transcriptoma
16.
Nat Commun ; 11(1): 4809, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968055

RESUMO

Kinase inhibitors (KIs) represent an important class of anti-cancer drugs. Although cardiotoxicity is a serious adverse event associated with several KIs, the reasons remain poorly understood, and its prediction remains challenging. We obtain transcriptional profiles of human heart-derived primary cardiomyocyte like cell lines treated with a panel of 26 FDA-approved KIs and classify their effects on subcellular pathways and processes. Individual cardiotoxicity patient reports for these KIs, obtained from the FDA Adverse Event Reporting System, are used to compute relative risk scores. These are then combined with the cell line-derived transcriptomic datasets through elastic net regression analysis to identify a gene signature that can predict risk of cardiotoxicity. We also identify relationships between cardiotoxicity risk and structural/binding profiles of individual KIs. We conclude that acute transcriptomic changes in cell-based assays combined with drug substructures are predictive of KI-induced cardiotoxicity risk, and that they can be informative for future drug discovery.


Assuntos
Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Perfilação da Expressão Gênica/métodos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Transcriptoma , Antineoplásicos/farmacologia , Cardiotoxicidade/tratamento farmacológico , Linhagem Celular , Relação Dose-Resposta a Droga , Aprovação de Drogas , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Análise de Regressão , Medição de Risco , Fatores de Risco , Alinhamento de Sequência , Estados Unidos , United States Food and Drug Administration
17.
Nat Commun ; 11(1): 4803, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968068

RESUMO

Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy. To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. Our data reveal that regional alterations in chromosome structure underlie clonal transcriptomic, epigenomic, and histopathologic signatures in meningioma. Stereotactic co-registration of sample coordinates to preoperative magnetic resonance images further suggest that high apparent diffusion coefficient (ADC) distinguishes meningioma regions with proliferating cells enriched for developmental gene expression programs. To understand the function of these genes in meningioma, we develop a human cerebral organoid model of meningioma and validate the high ADC marker genes CDH2 and PTPRZ1 as potential targets for meningioma therapy using live imaging, single cell RNA sequencing, CRISPR interference, and pharmacology.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Perfilação da Expressão Gênica/métodos , Heterogeneidade Genética , Imagem por Ressonância Magnética/métodos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/metabolismo , Idoso , Antígenos CD/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Caderinas/genética , Imagem de Difusão por Ressonância Magnética/métodos , Epigenômica , Feminino , Marcadores Genéticos , Genômica , Humanos , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/patologia , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Transcriptoma
18.
Nat Commun ; 11(1): 4830, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973134

RESUMO

Non-invasively probing metabolites within single live cells is highly desired but challenging. Here we utilize Raman spectro-microscopy for spatial mapping of metabolites within single cells, with the specific goal of identifying druggable metabolic susceptibilities from a series of patient-derived melanoma cell lines. Each cell line represents a different characteristic level of cancer cell de-differentiation. First, with Raman spectroscopy, followed by stimulated Raman scattering (SRS) microscopy and transcriptomics analysis, we identify the fatty acid synthesis pathway as a druggable susceptibility for differentiated melanocytic cells. We then utilize hyperspectral-SRS imaging of intracellular lipid droplets to identify a previously unknown susceptibility of lipid mono-unsaturation within de-differentiated mesenchymal cells with innate resistance to BRAF inhibition. Drugging this target leads to cellular apoptosis accompanied by the formation of phase-separated intracellular membrane domains. The integration of subcellular Raman spectro-microscopy with lipidomics and transcriptomics suggests possible lipid regulatory mechanisms underlying this pharmacological treatment. Our method should provide a general approach in spatially-resolved single cell metabolomics studies.


Assuntos
Melanoma/metabolismo , Metabolômica/métodos , Microscopia/métodos , Análise Espectral Raman/métodos , Apoptose , Linhagem Celular Tumoral , Ácidos Graxos/metabolismo , Humanos , Gotículas Lipídicas , Metabolismo dos Lipídeos , Lipidômica , Lipídeos , Ácido Oleico , Estearoil-CoA Dessaturase/metabolismo , Transcriptoma
19.
PLoS Biol ; 18(9): e3000783, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925907

RESUMO

Plant nucleotide-binding (NB) leucine-rich repeat (LRR) receptor (NLR) proteins function as intracellular immune receptors that perceive the presence of pathogen-derived virulence proteins (effectors) to induce immune responses. The 2 major types of plant NLRs that "sense" pathogen effectors differ in their N-terminal domains: these are Toll/interleukin-1 receptor resistance (TIR) domain-containing NLRs (TNLs) and coiled-coil (CC) domain-containing NLRs (CNLs). In many angiosperms, the RESISTANCE TO POWDERY MILDEW 8 (RPW8)-CC domain containing NLR (RNL) subclass of CNLs is encoded by 2 gene families, ACTIVATED DISEASE RESISTANCE 1 (ADR1) and N REQUIREMENT GENE 1 (NRG1), that act as "helper" NLRs during multiple sensor NLR-mediated immune responses. Despite their important role in sensor NLR-mediated immunity, knowledge of the specific, redundant, and synergistic functions of helper RNLs is limited. We demonstrate that the ADR1 and NRG1 families act in an unequally redundant manner in basal resistance, effector-triggered immunity (ETI) and regulation of defense gene expression. We define RNL redundancy in ETI conferred by some TNLs and in basal resistance against virulent pathogens. We demonstrate that, in Arabidopsis thaliana, the 2 RNL families contribute specific functions in ETI initiated by specific CNLs and TNLs. Time-resolved whole genome expression profiling revealed that RNLs and "classical" CNLs trigger similar transcriptome changes, suggesting that RNLs act like other CNLs to mediate ETI downstream of sensor NLR activation. Together, our genetic data confirm that RNLs contribute to basal resistance, are fully required for TNL signaling, and can also support defense activation during CNL-mediated ETI.


Assuntos
Arabidopsis/imunologia , Proteínas NLR/fisiologia , Imunidade Vegetal/genética , Receptores Imunológicos/fisiologia , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/fisiologia , Resistência à Doença/genética , Resistência à Doença/imunologia , Regulação da Expressão Gênica de Plantas , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Família Multigênica/genética , Família Multigênica/fisiologia , Proteínas NLR/genética , Doenças das Plantas/genética , Doenças das Plantas/imunologia , Plantas Geneticamente Modificadas , Receptores Imunológicos/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Transcriptoma
20.
PLoS One ; 15(9): e0237529, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941426

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic fibrotic lung disease with an irreversible decline of lung function. "Bronchiolization", characterized by ectopic appearance of airway epithelial cells in the alveolar regions, is one of the characteristic features in the IPF lung. Based on the knowledge that club cells are the major epithelial secretory cells in human small airways, and their major secretory product uteroglobin (SCGB1A1) is significantly increased in both serum and epithelial lining fluid of IPF lung, we hypothesize that human airway club cells contribute to the pathogenesis of IPF. By assessing the transcriptomes of the single cells from human lung of control donors and IPF patients, we identified two SCGB1A1+ club cell subpopulations, highly expressing MUC5B, a significant genetic risk factor strongly associated with IPF, and SCGB3A2, a marker heterogeneously expressed in the club cells, respectively. Interestingly, the cellular proportion of SCGB1A1+MUC5B+ club cells was significantly increased in IPF patients, and this club cell subpopulation highly expressed genes related to mucous production and immune cell chemotaxis. In contrast, though the cellular proportion did not change, the molecular phenotype of the SCGB1A1+SCGB3A2high club cell subpopulation was significantly altered in IPF lung, with increased expression of mucins, cytokine and extracellular matrix genes. The single cell transcriptomic analysis reveals the cellular and molecular heterogeneity of club cells, and provide novel insights into the biological functions of club cells in the pathogenesis of IPF.


Assuntos
Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Transcriptoma , Bronquíolos/citologia , Bronquíolos/patologia , Humanos , Fibrose Pulmonar Idiopática/genética , Pulmão/citologia , Mucosa Respiratória/citologia , Mucosa Respiratória/patologia , Secretoglobinas/genética , Análise de Célula Única , Uteroglobina/genética
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