ConsensusPathDB: toward a more complete picture of cell biology

Kamburov, Atanas; Pentchev, Konstantin; Galicka, Hanna; Wierling, Christoph; Lehrach, Hans; Herwig, Ralf

doi:10.1093/nar/gkq1156

Cited by 553 publications

(505 citation statements)

References 30 publications

(37 reference statements)

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“…In order to explore their functional relationship, we performed an enrichment analysis of Gene Ontology categories and visualized over-represented terms in a concept overlap graph using ConsensusPathDB. 26,27 Consistent with our previous observations, repressed genes were involved in epithelial development, proliferation and differentiation as well as several processes related to cellular adhesion, including wound healing, migration and extracellular matrix (ECM) organization (Fig. 1C and ref.…”

Section: Resultssupporting

confidence: 91%

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

et al. 2016

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Apoptosis caused by deregulated MYC expression is a prototype example of intrinsic tumor suppression. However, it is still unclear how supraphysiological MYC expression levels engage specific sets of target genes to promote apoptosis. Recently, we demonstrated that repression of SRF target genes by MYC/MIZ1 complexes limits AKT-dependent survival signaling and contributes to apoptosis induction. Here we report that supraphysiological levels of MYC repress gene sets that include markers of basal-like breast cancer cells, but not luminal cancer cells, in a MIZ1-dependent manner. Furthermore, repressed genes are part of a conserved gene signature characterizing the basal subpopulation of both murine and human mammary gland. These repressed genes play a role in epithelium and mammary gland development and overlap with genes mediating cell adhesion and extracellular matrix organization. Strikingly, acute activation of oncogenic MYC in basal mammary epithelial cells is sufficient to induce luminal cell identity markers. We propose that supraphysiological MYC expression impacts on mammary epithelial cell identity by repressing lineage-specific target genes. Such abrupt cell identity switch could interfere with adhesiondependent survival signaling and thus promote apoptosis in pre-malignant epithelial tissue.

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Section: Resultssupporting

confidence: 91%

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

et al. 2016

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“…The number of differentially expressed probes is often higher than the number of DEGs, as one gene is often represented by several probes. Genes within the Venn clusters and hierarchical cluster heatmaps were extracted and further analyzed again using the ConsensusPathDB database (Kamburov et al, 2011) and the Database for Annotation, Visualization and Integrated Discovery (DAVID) (Dennis et al, 2003) to assess significance for overrepresentation of DEGs in biological processes. Pathways with a p value 0.01 and a FDR 0.25 were considered as significantly regulated.…”

Section: Venn Mapping Hierarchical Clustering and Pathway Analysismentioning

confidence: 99%

Different responses of Caco-2 and MCF-7 cells to silver nanoparticles are based on highly similar mechanisms of action

et al. 2016

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The mode of action of silver nanoparticles (AgNPs) is suggested to be exerted through both Ag + and AgNP dependent mechanisms. Ingestion is one of the major NP exposure routes, and potential effects are often studied using Caco-2 cells, a well-established model for the gut epithelium. MCF-7 cells are epithelial breast cancer cells with extensive well-characterized toxicogenomics profiles. In the present study, we aimed to gain a deeper understanding of the cellular molecular responses in Caco-2 and MCF-7 cells after AgNP exposure in order to evaluate whether epithelial cells derived from different tissues demonstrated similar responses. These insights could possibly reduce the size of cell panels for NP hazard identification screening purposes. AgNPs of 20, 30, 60, and 110 nm, and AgNO 3 were exposed for 6 h and 24 h. AgNPs were shown to be taken up and dissolve intracellularly. Compared with MCF-7 cells, Caco-2 cells showed a higher sensitivity to AgNPs, slower gene expression kinetics and absence of NP size-dependent responses. However, on a molecular level, no significant differences were observed between the two cell types. Transcriptomic analysis showed that Ag(NP) exposure caused (oxidative) stress responses, possibly leading to cell death in both cell lines. There was no indication for effects specifically induced by AgNPs. Responses to AgNPs appeared to be induced by silver ions released from the AgNPs. In conclusion, differences in mRNA responses to AgNPs between Caco-2 and MCF-7 cells were mainly related to timing and magnitude, but not to a different underlying mechanism.

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“…To test for functional relationships between these genes, we looked for their co-occurrence within consensus reference pathways and protein -protein interaction networks (46). We also tested for co-regulation by specific microRNAs (47).…”

Section: Pathwaysmentioning

confidence: 99%

“…We used ConsensusPathDB (http://cpdb.molgen.mpg.de/), a human meta-database of 30 public repositories of biological interaction data hosted by the Max Planck Institute of Molecular Genetics in Berlin, Germany (46), plus data from TargetScan 5.1 for microRNA binding (47). To perform enrichment analysis, a hypergeometric test was performed to calculate the significance of the overlap between the genes from our input list (all genes +10 kb from DMRs with q-values of ,0.1 in the MWAS) and those present in each reference pathway, network or micro-RNA target list.…”

Section: Pathway Network Neighborhood and Microrna Analysismentioning

confidence: 99%

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

McClay¹,

Åberg²,

Clark³

et al. 2013

Human Molecular Genetics

149

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The central importance of epigenetics to the aging process is increasingly being recognized. Here we perform a methylome-wide association study (MWAS) of aging in whole blood DNA from 718 individuals, aged 25 -92 years (mean 5 55). We sequenced the methyl-CpG-enriched genomic DNA fraction, averaging 67.3 million reads per subject, to obtain methylation measurements for the ∼27 million autosomal CpGs in the human genome. Following extensive quality control, we adaptively combined methylation measures for neighboring, highly-correlated CpGs into 4 344 016 CpG blocks with which we performed association testing. Eleven age-associated differentially methylated regions (DMRs) passed Bonferroni correction (P-value < 1.15 3 10 28 ). Top findings replicated in an independent sample set of 558 subjects using pyrosequencing of bisulfite-converted DNA (min P-value < 10 230 ). To examine biological themes, we selected 70 DMRs with false discovery rate of <0.1. Of these, 42 showed hypomethylation and 28 showed hypermethylation with age. Hypermethylated DMRs were more likely to overlap with CpG islands and shores. Hypomethylated DMRs were more likely to be in regions associated with polycomb/regulatory proteins (e.g. EZH2) or histone modifications H3K27ac, H3K4m1, H3K4m2, H3K4m3 and H3K9ac. Among genes implicated by the top DMRs were protocadherins, homeobox genes, MAPKs and ryanodine receptors. Several of our DMRs are at genes with potential relevance for age-related disease. This study successfully demonstrates the application of next-generation sequencing to MWAS, by interrogating a large proportion of the methylome and returning potentially novel age DMRs, in addition to replicating several loci implicated in previous studies using microarrays.

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ConsensusPathDB: toward a more complete picture of cell biology

Cited by 553 publications

References 30 publications

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

Different responses of Caco-2 and MCF-7 cells to silver nanoparticles are based on highly similar mechanisms of action

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

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