scholarly journals Convergent rewiring of the virulence regulatory network promotes adaptation of Ralstonia solanacearum on resistant tomato

2020 ◽  
Author(s):  
Rekha Gopalan-Nair ◽  
Marie-Françoise Jardinaud ◽  
Ludovic Legrand ◽  
David Landry ◽  
Xavier Barlet ◽  
...  
Keyword(s):  
Ralstonia Solanacearum ◽  
Regulatory Network ◽  
Genomic Sequence ◽  
Quantitative Resistance ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genetic Alterations ◽  
Adaptive Potential ◽  
Tomato Cultivar ◽  
Genomic Polymorphism

Abstract The evolutionary and adaptive potential of a pathogen is a key determinant for successful host colonization and proliferation, but remains poorly known for most of the pathogens. Here, we used experimental evolution combined with phenotyping, genomics and transcriptomics to estimate the adaptive potential of the bacterial plant pathogen Ralstonia solanacearum to overcome the quantitative resistance of the tomato cultivar Hawaii 7996. After serial passaging over 300 generations, we observed pathogen adaptation to within-plant environment of the resistant cultivar but no plant resistance breakdown. Genomic sequence analysis of the adapted clones revealed few genetic alterations but we provide evidence that all but one were gain of function mutations. Transcriptomic analyses revealed that even if different adaptive events occurred in independently evolved clones, there is convergence towards a global rewiring of the virulence regulatory network as evidenced by largely overlapping gene expression profiles. A subset of four transcription regulators, including HrpB, the activator of the type 3 secretion system regulon and EfpR, a global regulator of virulence and metabolic functions, emerged as key nodes of this regulatory network that are frequently targeted to redirect the pathogen’s physiology and improve its fitness in adverse conditions. Significant transcriptomic variations were also detected in evolved clones showing no genomic polymorphism, suggesting that epigenetic modifications regulate expression of some of the virulence network components and play a major role in adaptation as well.

scholarly journals Integrated bioinformatics analysis reveals ASPM and CENPF with prognostic value in lung cancer

2019 ◽  
Author(s):  
jinghang li ◽  
Jing Zhang ◽  
Lin Huang ◽  
Sheng Zhao
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Cell Cycle ◽  
Expression Profiles ◽  
Mirna Gene ◽  
Gene Expression Profiles ◽  
Genetic Alterations ◽  
Potential Candidate ◽  
Expression Microarrays ◽  
Regulation Of Cell Cycle

Abstract Lung cancer (LC) is the most frequent type of cancer in the world. But the mechanism of LC is still largely unknown. In this study, we analyzed three lung cancer gene expression microarrays of different pathologic types to explore the potential candidate genes in LC by Integrated bioinformatical methods. 459 overlapped differentially expressed genes (DEGs) were explored in three GEO gene expression profiles of different pathologic types of lung cancer and function annotation of DEGs were performed. The main biological process of DEGs was regulation of vasculature development and angiogenesis. The most significant molecular function of DEGs was TGF-β receptor activity. The most significant Reactome pathway of DEGs was cell cycle and extracellular matrix organization pathway. The PPI network of the DEGs was constructed and 23 candidate hub genes were identified in the network . Kaplan-Meier survival analysis show 21 genes were associated with the prognosis of LC. The genetic alterations analysis of these genes by using cBioPortal shown ASPM has the highest genetic alteration rate of 9% in main pathological types of 3191 LC patients , CENPF has the second highest alteration rate of 6% in LC patients. ASPM and CENPF also identified have a significant co-occurrence relationship in LC, and the GO analysis shown they both participate in the regulation of cell cycle. In the TF -miRNA-gene network of 21 genes shown CENPF have the most significant value in the network and the most relevant TF are NFYA, E2F1 and MYC.In conclusion, this study explored several key genes about LC and analyzed potential TF of those genes, provides possible therapeutic targets and biomarker for further clinical application.

scholarly journals GENE-47. A 3D ATLAS TO EVALUATE THE SPATIAL PATTERNING OF GENETIC ALTERATIONS AND TUMOR CELL STATES IN GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi107-vi108
Author(s):  
Stephanie Hilz ◽  
Chibo Hong ◽  
Llewellyn Jalbert ◽  
Tali Mazor ◽  
Michael Martin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Genetic Alterations ◽  
Cell Populations ◽  
Low Grade ◽  
Lower Grade ◽  
Diffuse Glioma ◽  
Spatial Patterning

Abstract BACKGROUND Previous studies of solid tumors have been restricted in their ability to map how heterogeneous cell populations evolved within the tumor in three-dimensional (3D) space due to insufficient sampling, typically one sample per tumor, and a lack of knowledge of where within the tumor the sample was obtained. Knowledge of the extensivity of heterogeneity and how it is spatially distributed is crucial for assessing whether a therapeutic target is truly tumor-wide, and for exploring how mutations relate to heterogeneity in the local microenvironment. METHODS We developed a novel platform to integrate and visualize in 3D multi-omics data generated from each of 8–10 spatially mapped samples per tumor. Together, the 171 samples collected using this approach from 16 adult diffuse glioma at diagnosis and recurrence form a novel resource – the 3D Glioma Atlas. RESULTS By maximally sampling the tumor geography without excluding samples based on low cancer cell fraction (CCF), we identify a subpopulation of glioblastoma with pervasively lower CCF likely excluded by other atlases, such as the TCGA, that used stringent CCF cutoffs. Exome sequencing of 3D-mapped samples from lower-grade tumors revealed that clonal expansions are typically spatially segregated, implying minimal tumor-wide intermixing of genetically heterogenous cells. Heterogeneity is less spatially segregated for faster-growing high-grade tumors, suggesting that cell populations expand in these tumors differently. Recurrent low-grade tumors have greater intratumoral mutational heterogeneity than newly diagnosed tumors, though this did not translate into greater dissimilarity in gene expression profiles for recurrent tumors, suggesting minimal functional impact of this additional mutational diversity on gene expression. CONCLUSIONS The delineation of spatial patterns of heterogeneity that our work provides enables more informed interpretation of biopsies and greater insight into the factors shaping intratumoral variation of gene expression patterns. Ongoing work is exploring the spatial patterning of amplification events and the tumor microenvironment.

A comprehensive view of the structure and expression of the ependymoma genome at presentation and relapse

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2073-2073
Author(s):  
K. D. Wright ◽  
V. Rand ◽  
S. E. Leary ◽  
S. Mack ◽  
B. Coyle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mirna Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genetic Alterations ◽  
Specific Gene ◽  
Mortality And Morbidity ◽  
Distinct Subgroup ◽  
Comprehensive View ◽  
Genomic Study

2073 Background: Although pediatric and adult ependymomas are associated with significant mortality and morbidity, little is known about the biology of these tumors. To identify underlying genetic alterations and cellular pathways that drive this disease, we conducted a genomic study of 200 adult and pediatric ependymomas. Methods: Using 500k single nucleotide polymorphism arrays, U133 Affymetrix gene and microRNA (miRNA) expression microarrays, and appropriate bioinformatics, we characterized 56 supratentorial (ST), 104 posterior fossa (PF), and 40 spinal (SP) ependymomas. Real-Time polymerase chain reaction and fluorescence in situ hybridization validated observed genetic events. Results: Gene expression profiles segregated tumors by site and identified disease subgroups within each anatomical region (4 ST, 4 PF, 1 SP). miRNA expression profiles identified these same subgroups, indicating that they are biologically distinct. Subgroup-specific gene expression profiles were dictated partly by developmental regulatory genes and partly by large chromosomal gains (eg. 1q, 5p, 16p) and losses (eg. 9p, 22q). Integrated genetic and expression mapping revealed key candidate tumor suppressor (TSG) and onco- genes, likely drivers of these large alterations. While large chromosomal changes occurred more frequently in SP tumors (p < 0.0001), ST tumors averaged more focal changes (n = 13.2) than PF (n = 6.2) or SP tumors (n = 3.0) (p < 0.0001). A total of 29 and 33 non-random focal amplifications and deletions, respectively, encompassing 402 known genes and miRNA clusters, were validated, of which 80 displayed copy number driven expression. These genetic alterations targeted specific cellular functions (e.g., cell adhesion, cell-cycle, neuronal development) and pathways (e.g., NOTCH, EPHRIN, TP53). Our cohort also included five sample sets consisting of primary tumor and at least two corresponding relapses. Genomic analysis of these tumors identified large chromosomal alterations as well as focal gains and losses associated with disease relapse. Conclusions: We present a highly comprehensive view of the ependymoma genome, including 80 previously unrecognized candidate TSG and oncogenes that may afford diagnostic and therapeutic targets. No significant financial relationships to disclose.

Epigenetic tête-à-tête: the bilateral relationship between chromatin modifications and DNA methylationThis paper is one of a selection of papers published in this Special Issue, entitled 27th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process.

2006 ◽  
Vol 84 (4) ◽  
pp. 463-466 ◽  
Author(s):  
Ana C. D’Alessio ◽  
Moshe Szyf
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
De Novo ◽  
Peer Review Process ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cellular Transformation ◽  
Genetic Alterations ◽  
Covalent Modification ◽  
Associated Proteins

The epigenome, which comprises chromatin, associated proteins, and the pattern of covalent modification of DNA by methylation, sets up and maintains gene expression programs. It was originally believed that DNA methylation was the dominant reaction in determining the chromatin structure. However, emerging data suggest that chromatin can affect DNA methylation in both directions, triggering either de novo DNA methylation or demethylation. These events are particularly important for the understanding of cellular transformation, which requires a coordinated change in gene expression profiles. While genetic alterations can explain some of the changes, the important role of epigenetic reprogramming is becoming more and more evident. Cancer cells exhibit a paradoxical coexistence of global loss of DNA methylation with regional hypermethylation.

scholarly journals Genetic and pharmacological inactivation of adenosine A2A receptor reveals an Egr-2-mediated transcriptional regulatory network in the mouse striatum

2005 ◽  
Vol 23 (1) ◽  
pp. 89-102 ◽  
Author(s):  
Liqun Yu ◽  
Peter M. Haverty ◽  
Juliana Mariani ◽  
Yumei Wang ◽  
Hai-Ying Shen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Network ◽  
Molecular Mechanisms ◽  
Transcriptional Regulatory Network ◽  
Expression Profiles ◽  
Mrna Level ◽  
Gene Expression Profiles ◽  
Bioinformatics Analyses ◽  
Mouse Striatum ◽  
Transcriptional Regulatory

The adenosine A2A receptor (A2AR) is highly expressed in the striatum, where it modulates motor and emotional behaviors. We used both microarray and bioinformatics analyses to compare gene expression profiles by genetic and pharmacological inactivation of A2AR and inferred an A2AR-controlled transcription network in the mouse striatum. A comparison between vehicle (VEH)-treated A2AR knockout (KO) mice (A2AR KO-VEH) and wild-type (WT) mice (WT-VEH) revealed 36 upregulated genes that were partially mimicked by treatment with SCH-58261 (SCH; an A2AR antagonist) and 54 downregulated genes that were not mimicked by SCH treatment. We validated the A2AR as a specific drug target for SCH by comparing A2AR KO-SCH and A2AR KO-VEH groups. The unique downregulation effect of A2AR KO was confirmed by comparing A2AR KO-SCH with WT-SCH gene groups. The distinct striatal gene expression profiles induced by A2AR KO and SCH should provide clues to the molecular mechanisms underlying the different phenotypes observed after genetic and pharmacological inactivation of A2AR. Furthermore, bioinformatics analysis discovered that Egr-2 binding sites were statistically overrepresented in the proximal promoters of A2AR KO-affected genes relative to the unaffected genes. This finding was further substantiated by the demonstration that the Egr-2 mRNA level increased in the striatum of both A2AR KO and SCH-treated mice and that striatal Egr-2 binding activity in the promoters of two A2AR KO-affected genes was enhanced in A2AR KO mice as assayed by chromatin immunoprecipitation. Taken together, these results strongly support the existence of an Egr-2-directed transcriptional regulatory network controlled by striatal A2ARs.

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