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1.
Pestic Biochem Physiol ; 159: 98-106, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400791

RESUMO

The cotton aphid, Aphis gossypii Glover, is a destructive global crop pest. Control of A. gossypii has relied heavily on the application of chemical insecticides. The cotton aphid has developed resistance to numerous insecticides, including imidacloprid, which has been widely used to control cotton pests in China since the 1990s. Our objective was to investigate the potential role of UDP-glycosyltransferases (UGTs) in imidacloprid resistance based on transcriptomic and proteomic analyses of field-originated imidacloprid-resistant (IMI_R) and -susceptible (IMI_S) A. gossypii clones. The transcriptomic and proteomic analyses revealed that 12 out of 512 differentially expressed genes and three out of 510 differentially expressed proteins were predicted as UDP-glycosyltransferase (UGT). Based on quantitative real-time PCR analysis, nine UGT genes, UGT343A4, UGT344A15, UGT344A16, UGT344B4, UGT344C7, UGT344C9, UGT344N4, UGT 24541, and UGT7630, were up-regulated in the IMI_R clone compared to the IMI_S clone. Meanwhile, UGT344A16, UGT344B4, UGT344C7, and UGT344N4 were overexpressed at the protein level based on western blot analysis. Furthermore, knockdown of UGT344B4 or UGT344C7 using RNA interference (RNAi) significantly increased sensitivity to imidacloprid in the IMI_R clone. In conclusion, UGTs potentially contributed to imidacloprid resistance in A. gossypii originating from cotton-growing regions of China. These results provide insights into the way we study insecticide resistance in cotton aphids.


Assuntos
Afídeos/efeitos dos fármacos , Glucosiltransferases/metabolismo , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Animais , Afídeos/genética , Afídeos/metabolismo , Glucosiltransferases/genética , Resistência a Inseticidas/genética , Proteômica , Transcriptoma/genética
2.
J Cancer Res Clin Oncol ; 145(9): 2325-2333, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31317326

RESUMO

PURPOSE: Nodal positive lung adenocarcinoma includes wide range of survival. Several methods for the classification of nodal-positive lung cancer have been proposed. However, classification considering the impact of targetable genetic variants are lacking. The possibility of genetic variants for the better stratification of nodal positive lung adenocarcinoma was estimated. METHODS: Mutations of 36 genes between primary sites and metastatic lymph nodes (LNs) were compared using next-generation sequencing. Subsequently, mutations in EGFR and BRAF, rearrangements in ALK and ROS1 were evaluated in 69 resected pN1-2M0 adenocarcinoma cases. Recurrence-free survival (RFS), post-recurrence survival (PRS), and overall survival (OS) were evaluated with respect to targetable variants and tyrosine kinase inhibitor (TKI) therapy after recurrence. RESULTS: About 90% of variants were shared and allele frequencies were similar between primary and metastatic sites. In 69 pN1-2M0 cases, EGFR/ALK were positive in primary sites of 39 cases and same EGFR/ALK variants were confirmed in metastatic LNs of 96.7% tissue-available cases. Multivariate analyses indicated positive EGFR/ALK status was associated with worse RFS (HR 2.366; 95% CI 1.244-4.500; P = 0.009), and PRS was prolonged in cases receiving TKI therapy (no post-recurrence TKI therapies, HR 3.740; 95% CI 1.449-9.650; P = 0.006). OS did not differ with respect to targetable variants or TKI therapy. CONCLUSIONS: Cases harbouring targetable genetic variants had a higher risk of recurrence, but PRS was prolonged by TKI therapy. Classification according to the targetable genetic status provides a basis for predicting recurrence and determining treatment strategies after recurrence.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Neoplasias Pulmonares/diagnóstico , Pulmão/metabolismo , Linfonodos/metabolismo , Mutação , Transcriptoma/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Metástase Linfática , Masculino , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos
3.
Medicine (Baltimore) ; 98(27): e16273, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277152

RESUMO

BACKGROUND: Although the outcome of patients with gastric cancer (GC) has improved significantly with the recent implementation of annual screening programs. Reliable prognostic biomarkers are still needed due to the disease heterogeneity. Increasing pieces of evidence revealed an association between immune signature and GC prognosis. Thus, we aim to build an immune-related signature that can estimate prognosis for GC. METHODS: For identification of a prognostic immune-related gene signature (IRGS), gene expression profiles and clinical information of patients with GC were collected from 3 public cohorts, divided into training cohort (n = 300) and 2 independent validation cohorts (n = 277 and 433 respectively). RESULTS: Within 1811 immune genes, a prognostic IRGS consisting of 16 unique genes was constructed which was significantly associated with survival (hazard ratio [HR], 3.9 [2.78-5.47]; P < 1.0 × 10). In the validation cohorts, the IRGS significantly stratified patients into high- vs low-risk groups in terms of prognosis across (HR, 1.84 [1.47-2.30]; P = 6.59 × 10) and within subpopulations with stage I&II disease (HR, 1.96 [1.34-2.89]; P = 4.73 × 10) and was prognostic in univariate and multivariate analyses. Several biological processes, including TGF-ß and EMT signaling pathways, were enriched in the high-risk group. T cells CD4 memory resting and Macrophage M2 were significantly higher in the high-risk risk group compared with the low-risk group. CONCLUSION: In short, we developed a prognostic IRGS for estimating prognosis in GC, including stage I&II disease, providing new insights into the identification of patients with GC with a high risk of mortality.


Assuntos
Biomarcadores Tumorais/imunologia , DNA de Neoplasias/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/genética , Transcriptoma/genética , Biomarcadores Tumorais/genética , DNA de Neoplasias/imunologia , Feminino , Humanos , Masculino , Prognóstico , Fatores de Risco , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo
4.
Cytogenet Genome Res ; 158(3): 133-144, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31272101

RESUMO

Bone morphogenetic protein 2 (BMP2) can mediate the signaling of R-Smads and regulate different biological functions, including adipocyte differentiation. Long noncoding RNAs (lncRNAs) can be involved in many important biological processes, including fat metabolism, as miRNA sponges. This study aimed to investigate the molecular mechanism of fat deposition and to provide useful information for the prevention and treatment of lipid-related diseases. lncRNA sequencing was performed to compare and analyze, for the first time, the expression of lncRNAs in BMP2-induced and non-BMP2-induced preadipocytes from Junmu1 pigs. In addition, functional annotation and enrichment analysis of differentially expressed lncRNA target genes were carried out. lncRNAs and mRNAs were compared and analyzed. lncRNAs were identified that may regulate adipogenesis and lipid metabolism. The results give a theoretical basis for further studies on fat deposition mechanisms and provide potential therapeutic targets for metabolic diseases.


Assuntos
Adipócitos/efeitos dos fármacos , Proteína Morfogenética Óssea 2/farmacologia , Diferenciação Celular/efeitos dos fármacos , RNA Longo não Codificante/análise , Células-Tronco/efeitos dos fármacos , Suínos/genética , Transcriptoma/genética , Adipócitos/citologia , Adipócitos/metabolismo , Animais , RNA Longo não Codificante/genética , Análise de Sequência de RNA , Células-Tronco/citologia , Células-Tronco/metabolismo , Triglicerídeos/metabolismo
5.
Life Sci ; 232: 116614, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260682

RESUMO

AIMS: SRY-box 18 (SOX18) is a transcription factor known for its role in regulating cell differentiation and lymphatic and blood vessel development. It has been reported that SOX18 was involved in various diseases, including cancer. This study aimed to explore the significance and biological function of SOX18 in bladder cancer (BCa). MATERIALS AND METHODS: SOX18 expression in BCa and normal tissues was analyzed by immunohistochemistry, and SOX18 expression in BCa cell lines was quantified by western blotting and quantitative real-time PCR. The role of SOX18 on the proliferation, migration and invasion of BCa cells was explored by CCK-8 and transwell invasion assays in vitro. Cell cycle was measured by flow cytometry assays. Western blotting and qRT-PCR were performed to investigate the potential mechanisms by which SOX18 leads to tumor progression. KEY FINDINGS: SOX18 was significantly upregulated in BCa and its expression was associated with clinical features of patients with BCa. Our data demonstrated that SOX18 promoted cell proliferation via accelerating cell cycle and by regulating c-Myc and Cyclin D1, promoted cell invasion via upregulation of MMP-7. Moreover, phosphorylation of c-Met and Akt regulated by SOX18 was identified to be involved in the process of cell migration and invasion, indicating the vital role of SOX18 in the metastasis of BCa. SIGNIFICANCE: Our data demonstrated a cancer-promoting effect of SOX18 in BCa, revealed the potential mechanisms of SOX18 in mediating cellular functions, and indicated that SOX18 may serve as a promising progression and prognostic biomarker and a therapeutic target for BCa.


Assuntos
Fatores de Transcrição SOXF/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Ciclina D1/metabolismo , Feminino , Fase G1/fisiologia , Xenoenxertos , Humanos , Masculino , Metaloproteinase 7 da Matriz/metabolismo , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fase S/fisiologia , Fatores de Transcrição SOXF/biossíntese , Fatores de Transcrição SOXF/genética , Transcriptoma/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
6.
Nature ; 571(7764): 205-210, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31270459

RESUMO

The mammalian brain contains neurogenic niches that comprise neural stem cells and other cell types. Neurogenic niches become less functional with age, but how they change during ageing remains unclear. Here we perform single-cell RNA sequencing of young and old neurogenic niches in mice. The analysis of 14,685 single-cell transcriptomes reveals a decrease in activated neural stem cells, changes in endothelial cells and microglia, and an infiltration of T cells in old neurogenic niches. T cells in old brains are clonally expanded and are generally distinct from those in old blood, which suggests that they may experience specific antigens. T cells in old brains also express interferon-γ, and the subset of neural stem cells that has a high interferon response shows decreased proliferation in vivo. We find that T cells can inhibit the proliferation of neural stem cells in co-cultures and in vivo, in part by secreting interferon-γ. Our study reveals an interaction between T cells and neural stem cells in old brains, opening potential avenues through which to counteract age-related decline in brain function.


Assuntos
Envelhecimento/fisiologia , Encéfalo/citologia , Movimento Celular , Células-Tronco Neurais/citologia , Neurogênese , Análise de Célula Única , Nicho de Células-Tronco/fisiologia , Linfócitos T/citologia , Animais , Sangue , Proliferação de Células , Células Clonais/citologia , Técnicas de Cocultura , Células Endoteliais/citologia , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Análise de Sequência de RNA , Transdução de Sinais , Linfócitos T/metabolismo , Transcriptoma/genética
7.
BMC Evol Biol ; 19(1): 149, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337330

RESUMO

BACKGROUND: Adenosine deaminase enzymes of the ADAR family are conserved in metazoans. They convert adenine into inosine in dsRNAs and thus alter both structural properties and the coding potential of their substrates. Acting on exogenous dsRNAs, ADAR1 exerts a pro- or anti-viral role in vertebrates and Drosophila. RESULTS: We traced 4 ADAR homologs in 14 lophotrochozoan genomes and we classified them into ADAD, ADAR1 or ADAR2, based on phylogenetic and structural analyses of the enzymatic domain. Using RNA-seq and quantitative real time PCR we demonstrated the upregulation of one ADAR1 homolog in the bivalve Crassostrea gigas and in the gastropod Haliotis diversicolor supertexta during Ostreid herpesvirus-1 or Haliotid herpesvirus-1 infection. Accordingly, we demonstrated an extensive ADAR-mediated editing of viral RNAs. Single nucleotide variation (SNV) profiles obtained by pairing RNA- and DNA-seq data from the viral infected individuals resulted to be mostly compatible with ADAR-mediated A-to-I editing (up to 97%). SNVs occurred at low frequency in genomic hotspots, denoted by the overlapping of viral genes encoded on opposite DNA strands. The SNV sites and their upstream neighbor nucleotide indicated the targeting of selected adenosines. The analysis of viral sequences suggested that, under the pressure of the ADAR editing, the two Malacoherpesviridae genomes have evolved to reduce the number of deamination targets. CONCLUSIONS: We report, for the first time, evidence of an extensive editing of Malacoherpesviridae RNAs attributable to host ADAR1 enzymes. The analysis of base neighbor preferences, structural features and expression profiles of molluscan ADAR1 supports the conservation of the enzyme function among metazoans and further suggested that ADAR1 exerts an antiviral role in mollusks.


Assuntos
Antivirais/metabolismo , Vírus de DNA/genética , Moluscos/virologia , Edição de RNA/genética , RNA Viral/genética , Proteínas de Ligação a RNA/metabolismo , Animais , Teorema de Bayes , Vírus de DNA/fisiologia , Regulação da Expressão Gênica , Genoma Viral , Modelos Moleculares , Moluscos/genética , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Domínios Proteicos , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Transcriptoma/genética
8.
Nature ; 571(7765): 355-360, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31270458

RESUMO

Defining the transcriptomic identity of malignant cells is challenging in the absence of surface markers that distinguish cancer clones from one another, or from admixed non-neoplastic cells. To address this challenge, here we developed Genotyping of Transcriptomes (GoT), a method to integrate genotyping with high-throughput droplet-based single-cell RNA sequencing. We apply GoT to profile 38,290 CD34+ cells from patients with CALR-mutated myeloproliferative neoplasms to study how somatic mutations corrupt the complex process of human haematopoiesis. High-resolution mapping of malignant versus normal haematopoietic progenitors revealed an increasing fitness advantage with myeloid differentiation of cells with mutated CALR. We identified the unfolded protein response as a predominant outcome of CALR mutations, with a considerable dependency on cell identity, as well as upregulation of the NF-κB pathway specifically in uncommitted stem cells. We further extended the GoT toolkit to genotype multiple targets and loci that are distant from transcript ends. Together, these findings reveal that the transcriptional output of somatic mutations in myeloproliferative neoplasms is dependent on the native cell identity.


Assuntos
Genótipo , Mutação , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Neoplasias/genética , Neoplasias/patologia , Transcriptoma/genética , Animais , Antígenos CD34/metabolismo , Calreticulina/genética , Linhagem Celular , Proliferação de Células , Células Clonais/classificação , Células Clonais/metabolismo , Células Clonais/patologia , Endorribonucleases/metabolismo , Hematopoese/genética , Células-Tronco Hematopoéticas/classificação , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Camundongos , Modelos Moleculares , Transtornos Mieloproliferativos/classificação , NF-kappa B/metabolismo , Neoplasias/classificação , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Resposta a Proteínas não Dobradas/genética
9.
Cell Mol Biol Lett ; 24: 38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182966

RESUMO

Background: Exploration of the genes with abnormal expression during the development of breast cancer is essential to provide a deeper understanding of the mechanisms involved. Transcriptome sequencing and bioinformatics analysis of invasive ductal carcinoma and paracancerous tissues from the same patient were performed to identify the key genes and signaling pathways related to breast cancer development. Methods: Samples of breast tumor tissue and paracancerous breast tissue were obtained from 6 patients. Sequencing used the Illumina HiSeq platform. All. Only perfectly matched clean reads were mapped to the reference genome database, further analyzed and annotated based on the reference genome information. Differentially expressed genes (DEGs) were identified using the DESeq R package (1.10.1) and DEGSeq R package (1.12.0). Using KOBAS software to execute the KEGG bioinformatics analyses, enriched signaling pathways of DEGs involved in the occurrence of breast cancer were determined. Subsequently, quantitative real time PCR was used to verify the accuracy of the expression profile of key DEGs from the RNA-seq result and to explore the expression patterns of novel cancer-related genes on 8 different clinical individuals. Results: The transcriptomic sequencing results showed 937 DEGs, including 487 upregulated and 450 downregulated genes in the breast cancer specimens. Further quantitative gene expression analysis was performed and captured 252 DEGs (201 downregulated and 51 upregulated) that showed the same differential expression pattern in all libraries. Finally, 6 upregulated DEGs (CST2, DRP2, CLEC5A, SCD, KIAA1211, DTL) and 6 downregulated DEGs (STAC2, BTNL9, CA4, CD300LG, GPIHBP1 and PIGR), were confirmed in a quantitative real time PCR comparison of breast cancer and paracancerous breast tissues from 8 clinical specimens. KEGG analysis revealed various pathway changes, including 20 upregulated and 21 downregulated gene enrichment pathways. The extracellular matrix-receptor (ECM-receptor) interaction pathway was the most enriched pathway: all genes in this pathway were DEGs, including the THBS family, collagen and fibronectin. These DEGs and the ECM-receptor interaction pathway may perform important roles in breast cancer. Conclusion: Several potential breast cancer-related genes and pathways were captured, including 7 novel upregulated genes and 76 novel downregulated genes that were not found in other studies. These genes are related to cell proliferation, movement and adhesion. They may be important for research into breast cancer mechanisms, particularly CST2 and CA4. A key signaling pathway, the ECM-receptor interaction signal pathway, was also identified as possibly involved in the development of breast cancer.


Assuntos
Neoplasias da Mama/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/genética , Regulação para Baixo/genética , Feminino , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Transcriptoma/genética , Regulação para Cima/genética
10.
Nat Commun ; 10(1): 2611, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197158

RESUMO

The abundance of new computational methods for processing and interpreting transcriptomes at a single cell level raises the need for in silico platforms for evaluation and validation. Here, we present SymSim, a simulator that explicitly models the processes that give rise to data observed in single cell RNA-Seq experiments. The components of the SymSim pipeline pertain to the three primary sources of variation in single cell RNA-Seq data: noise intrinsic to the process of transcription, extrinsic variation indicative of different cell states (both discrete and continuous), and technical variation due to low sensitivity and measurement noise and bias. We demonstrate how SymSim can be used for benchmarking methods for clustering, differential expression and trajectory inference, and for examining the effects of various parameters on their performance. We also show how SymSim can be used to evaluate the number of cells required to detect a rare population under various scenarios.


Assuntos
Perfilação da Expressão Gênica/métodos , Modelos Genéticos , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Análise por Conglomerados , Simulação por Computador , Conjuntos de Dados como Assunto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Cinética , Transcriptoma/genética
11.
Nat Commun ; 10(1): 2645, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201315

RESUMO

Lettuce downy mildew caused by Bremia lactucae is the most important disease of lettuce globally. This oomycete is highly variable and rapidly overcomes resistance genes and fungicides. The use of multiple read types results in a high-quality, near-chromosome-scale, consensus assembly. Flow cytometry plus resequencing of 30 field isolates, 37 sexual offspring, and 19 asexual derivatives from single multinucleate sporangia demonstrates a high incidence of heterokaryosis in B. lactucae. Heterokaryosis has phenotypic consequences on fitness that may include an increased sporulation rate and qualitative differences in virulence. Therefore, selection should be considered as acting on a population of nuclei within coenocytic mycelia. This provides evolutionary flexibility to the pathogen enabling rapid adaptation to different repertoires of host resistance genes and other challenges. The advantages of asexual persistence of heterokaryons may have been one of the drivers of selection that resulted in the loss of uninucleate zoospores in multiple downy mildews.


Assuntos
Núcleo Celular/genética , Interações Hospedeiro-Patógeno/genética , Alface/microbiologia , Oomicetos/genética , Doenças das Plantas/microbiologia , Núcleo Celular/efeitos dos fármacos , Resistência à Doença/genética , Fungicidas Industriais/farmacologia , Genômica , Alface/genética , Oomicetos/citologia , Oomicetos/patogenicidade , Seleção Genética/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Virulência/genética
12.
Nat Commun ; 10(1): 2764, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235699

RESUMO

Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAFV600E and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Transcriptoma/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Medicina de Precisão/métodos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genética , Análise de Sobrevida , Carcinoma Anaplásico da Tireoide/mortalidade , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/terapia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia , Regulação para Cima
13.
Cancer Sci ; 110(8): 2318-2327, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31187550

RESUMO

Precision medicine places significant emphasis on techniques for the identification of DNA mutations and gene expression by deep sequencing of gene panels to obtain medical data. However, other diverse information that is not easily readable using bioinformatics, including RNA modifications, has emerged as a novel diagnostic and innovative therapy owing to its multifunctional aspects. It is suggested that this breakthrough innovation might open new avenues for the elucidation of uncharacterized cancer cellular functions to develop more precise medical applications. The functional characteristics and regulatory mechanisms of RNA modifications, ie, the epitranscriptome (ETR), which reflects RNA metabolism, remains unclear, mainly due to detection methods being limited. Recent studies have revealed that N6-methyl adenosine, the most common modification in mRNA in eukaryotes, is affected in various types of cancer and, in some cases, cancer stem cells, but also affects cellular responses to viral infections. The ETR can control cancer cell fate through mRNA splicing, stability, nuclear export, and translation. Here we report on the recent progress of ETR detection methods, and biological findings regarding the significance of ETR in cancer precision medicine.


Assuntos
Neoplasias/genética , Transcriptoma/genética , Adenosina/análogos & derivados , Adenosina/genética , Animais , Eucariotos/genética , Humanos , Medicina de Precisão/métodos , RNA Mensageiro/genética
14.
Life Sci ; 232: 116547, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31176780

RESUMO

AIMS: This study aims to investigate the value of the expression of miR-208, miR-494, miR-499 and miR-1303 in the early diagnosis of acute myocardial infarction (AMI). MAIN METHODS: Patients were divided into two groups: AMI group (n = 41), and Stable angina pectoris (SAP) group (n = 32). Peripheral venous blood was sampled from these patients at the time of admission (T0), 6 h after onset (T6) and 12 h after onset (T12), while blood was sampled once from healthy subjects who underwent physical examination in the same time period (control group, n = 10). The expression of miR-208, miR-494, miR-499 and miR-1303 in serum were detected by real-time quantitative polymerase chain reaction (qRT-PCR), and differences in miRNA expression among these three groups of patients were analyzed. KEY FINDINGS: Serum miR-208, miR-494, miR-499 and miR-1303 expression levels at different time points were significantly higher in the AMI group than in the SAP group and control group. The differences among these groups were statistically significant (P < 0.05), while the difference between the SAP group and control group was not statistically significant (P > 0.05). Variation trend: The miRNA levels above began to increase at T0 in the AMI group, the peak levels of miR-208, miR-494 and miR-499 appeared before T12, and the peak level of miR-1303 appeared between T6 and T12, or after T12. SIGNIFICANCE: miR-208, miR-494, miR-499 and miR-1303 were not superior to hs-cTnI as myocardial markers in the diagnosis of early acute myocardial infarction.


Assuntos
MicroRNAs/genética , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Idoso , Angina Estável/genética , Angina Estável/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Diagnóstico Precoce , Feminino , Humanos , Masculino , MicroRNAs/análise , Pessoa de Meia-Idade , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma/genética , Troponina I/análise , Troponina I/sangue , Troponina T/análise , Troponina T/sangue
15.
Life Sci ; 232: 116596, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31233760

RESUMO

AIMS: The aim of the study was to identify key miRNAs related to hepatocellular carcinoma (HCC) and then to explore their potential function and clinical significance. MATERIALS AND METHODS: The miRNA expression profiles of 387 HCC and 62 normal liver tissues were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. GEO2R tool and edgeR package in R/Bioconductor were used to screen out HCC-related miRNAs. VennDiagram package was used to identify key miRNAs related to HCC. The miRWalk tool and multiple R packages, such as pROC and survival, were used to explore potential function and clinical significance of these key miRNAs. KEY FINDINGS: A total of 17 and 300 HCC-related human miRNAs were identified in GEO dataset and TCGA, respectively. Thereinto seven miRNAs including hsa-miR-199a-3p, hsa-miR-199b-3p, hsa-miR-139-5p, hsa-miR-139-3p, hsa-miR-424-3p, hsa-miR-1269b and hsa-miR-1269a were key miRNAs related to HCC. Functional enrichment analysis showed that these key miRNAs were involved in multiple biological processes, such as telomere maintenance via telomerase, protein sumoylation, histone mRNA metabolic process and angiotensin maturation. Cox regression analysis indicated that hsa-miR-139-5p expression was associated with the prognosis of HCC patients. ROC curve analysis suggested that survival prediction model developed based on tumor stage and hsa-miR-139-5p exhibited good performance in predicting 3-year overall survival of HCC patients. SIGNIFICANCE: The present study identified several HCC-related miRNAs, which might serve as new diagnostic markers and therapeutic targets for HCC. In addition, hsa-miR-139-5p might act as a promising prognostic indicator for HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , MicroRNAs/biossíntese , MicroRNAs/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/metabolismo , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Prognóstico , Curva ROC , Transcriptoma/genética
16.
Nature ; 571(7763): 107-111, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31217582

RESUMO

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.


Assuntos
Diarreia/congênito , Diarreia/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes , Intestinos/fisiologia , Deleção de Sequência/genética , Animais , Cromossomos Humanos Par 16/genética , Modelos Animais de Doenças , Feminino , Genes Reporter , Loci Gênicos/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Linhagem , Fenótipo , Ativação Transcricional , Transcriptoma/genética , Transgenes/genética
17.
Aquat Toxicol ; 213: 105204, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31185427

RESUMO

Previous toxicological investigations of the insensitive munition (IM), 3-nitro-1,2,4-triazol-5-one (NTO), demonstrated histopathological and physiological impacts in mammalian testes. The implications of these findings for fish was unknown, therefore we investigated the effects of chronic (21 day) exposures to NTO and an NTO-containing IM formulation called IMX-101 (composed of 2,4-dinitroanisole (DNAN), nitroguanidine (NQ), and NTO) in adult male fathead minnows to assess if impacts on testes were conserved. The NTO exposure caused no significant mortality through the maximum exposure concentration (720 mg/L, measured), however NTO elicited testicular impacts causing significant asynchrony in spermatogenesis and necrosis in secondary spermatocytes at the two highest exposure concentrations (383 mg/L and 720 mg/L) and testicular degeneration at the highest exposure. Microarray-based transcriptomics analysis identified significant enrichment of steroid metabolism pathways and mTORC-signal control of spermatogonia differentiation in NTO exposures each having logical connections to observed asynchronous spermatogenesis. Additionally, NTO impaired transcriptional expression for genes supporting sperm structural and flagellar development including sperm-associated antigen 6 (Spag6). These functional transcriptomic responses are hypothesized contributors to impacted reproductive physiology in NTO exposures that ultimately lead to reductions in spermatozoa. In contrast to NTO, the IMX-101 formulation elicited significant mortality at the two highest exposure concentrations of 25.2 and 50.9 mg/L (DNAN nominal + NTO measured + NQ measured). Unlike NTO and NQ, the DNAN component of the IMX-101 formulation underwent significant transformation in the 21d exposure. From previous investigations, neither NTO nor NQ caused mortality in fish at >1000 mg/L suggesting that mortality in the present study arose from DNAN / DNAN-attributable transformation products. The 12.6 mg/L IMX-101 exposure caused significant sublethal impacts on testes including sperm necrosis, interstitial fibrosis, and Sertoli-like cell hyperplasia. Transcriptional profiles for IMX-101 indicated significant enrichment on multiple signaling pathways supporting spermatogenesis, mitosis / meiosis, and flagellar structure, all logically connected to observed sperm necrosis. Additionally, pronounced transcriptional increases within the PPARα-RXRα pathway, a known DNAN target, has been hypothesized to correspond to Sertoli cell hyperplasia, presumably as a compensatory response to fulfill the nurse-function of Sertoli cells during spermatogenesis. Overall, the transcriptional results indicated unique molecular responses for NTO and IMX-101. Regarding chemical hazard, NTO impacted testes and impaired spermatogenesis, but at high exposure concentrations (≥ 192 mg/L), whereas the IMX-101 formulation, elicited mortality and impacts on reproductive physiology likely caused by DNAN and its transformation products present at concentrations well below the NTO-component concentration within the IMX-101 mixture formulation.


Assuntos
Anisóis/toxicidade , Cyprinidae/fisiologia , Nitrocompostos/toxicidade , Testículo/fisiologia , Triazóis/toxicidade , Animais , Cyprinidae/genética , Masculino , Análise de Componente Principal , Reprodução/efeitos dos fármacos , Espermatogênese , Testículo/efeitos dos fármacos , Testículo/patologia , Transcriptoma/genética , Poluentes Químicos da Água/toxicidade
18.
Nature ; 571(7766): 505-509, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31243369

RESUMO

The evolution of gene expression in mammalian organ development remains largely uncharacterized. Here we report the transcriptomes of seven organs (cerebrum, cerebellum, heart, kidney, liver, ovary and testis) across developmental time points from early organogenesis to adulthood for human, rhesus macaque, mouse, rat, rabbit, opossum and chicken. Comparisons of gene expression patterns identified correspondences of developmental stages across species, and differences in the timing of key events during the development of the gonads. We found that the breadth of gene expression and the extent of purifying selection gradually decrease during development, whereas the amount of positive selection and expression of new genes increase. We identified differences in the temporal trajectories of expression of individual genes across species, with brain tissues showing the smallest percentage of trajectory changes, and the liver and testis showing the largest. Our work provides a resource of developmental transcriptomes of seven organs across seven species, and comparative analyses that characterize the development and evolution of mammalian organs.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Organogênese/genética , Transcriptoma/genética , Animais , Evolução Biológica , Galinhas/genética , Feminino , Humanos , Macaca mulatta/genética , Masculino , Camundongos , Gambás/genética , Coelhos , Ratos
19.
BMC Plant Biol ; 19(1): 193, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072347

RESUMO

BACKGROUND: Wheat production is largely restricted by adverse environmental stresses. Under many undesirable conditions, endoplasmic reticulum (ER) stress can be induced. However, the physiological and molecular responses of wheat to ER stress remain poorly understood. We used dithiothreitol (DTT) and tauroursodeoxycholic acid (TUDCA) to induce or suppress ER stress in wheat cells, respectively, with the aim to reveal the molecular background of ER stress responses using a combined approach of transcriptional profiling and morpho-physiological characterization. METHODS: To understand the mechanism of wheat response to ER stress, three wheat cultivars were used in our pre-experiments. Among them, the cultivar with a moderate stress tolerance, Yunong211 was used in the following experiments. We used DTT (7.5 mM) to induce ER stress and TUDCA (25 µg·mL- 1) to suppress the stress. Under three treatment groups (Control, DTT and DTT + TUDCA), we firstly monitored the morphological, physiological and cytological changes of wheat seedlings. Then we collected leaf samples from each group for RNA extraction, library construction and RNA sequencing on an Illumina Hiseq platform. The sequencing data was then validated by qRT-PCR. RESULTS: Morpho-physiological results showed DTT significantly reduced plant height and biomass, decreased contents of chlorophyll and water, increased electrolyte leakage rate and antioxidant enzymes activity, and accelerated the cell death ratio, whereas these changes were all remarkably alleviated after TUDCA co-treatment. Therefore, RNA sequencing was performed to determine the genes involved in regulating wheat response to stress. Transcriptomic analysis revealed that 8204 genes were differentially expressed in three treatment groups. Among these genes, 158 photosynthesis-related genes, 42 antioxidant enzyme genes, 318 plant hormone-related genes and 457 transcription factors (TFs) may play vital roles in regulating wheat response to ER stress. Based on the comprehensive analysis, we propose a hypothetical model to elucidate possible mechanisms of how plants adapt to environmental stresses. CONCLUSIONS: We identified several important genes that may play vital roles in wheat responding to ER stress. This work should lay the foundations of future studies in plant response to environmental stresses.


Assuntos
Estresse do Retículo Endoplasmático/genética , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Transcriptoma/genética , Triticum/genética , Triticum/fisiologia , Ditiotreitol/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Ontologia Genética , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/genética , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Ácido Tauroquenodesoxicólico/farmacologia , Fatores de Transcrição/metabolismo , Transcriptoma/efeitos dos fármacos , Triticum/anatomia & histologia
20.
Nat Commun ; 10(1): 2046, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053723

RESUMO

Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. Here we perform a multi-omics study of neurons isolated from the prefrontal cortex in schizophrenia and bipolar disorder (n = 55 cases and 27 controls). DNA methylation, transcriptomic, and genetic-epigenetic interactions in major psychosis converged on pathways of neurodevelopment, synaptic activity, and immune functions. We observe prominent hypomethylation of an enhancer within the insulin-like growth factor 2 (IGF2) gene in major psychosis neurons. Chromatin conformation analysis revealed that this enhancer targets the nearby tyrosine hydroxylase (TH) gene responsible for dopamine synthesis. In patients, we find hypomethylation of the IGF2 enhancer is associated with increased TH protein levels. In mice, Igf2 enhancer deletion disrupts the levels of TH protein and striatal dopamine, and induces transcriptional and proteomic abnormalities affecting neuronal structure and signaling. Our data suggests that epigenetic activation of the enhancer at IGF2 may enhance dopamine synthesis associated with major psychosis.


Assuntos
Transtorno Bipolar/genética , Dopamina/biossíntese , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Fator de Crescimento Insulin-Like II/genética , Esquizofrenia/genética , Tirosina 3-Mono-Oxigenase/genética , Adulto , Idoso , Animais , Transtorno Bipolar/patologia , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neurônios/patologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/patologia , Proteômica , Esquizofrenia/patologia , Transcriptoma/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Adulto Jovem
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