g:Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments

Reimand, Jüri; Kull, Meelis; Peterson, Hedi; Hansen, Jaanus; Vilo, Jaak

doi:10.1093/nar/gkm226

Cited by 1,189 publications

(1,115 citation statements)

References 26 publications

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“…Differential SEs associated genes in ependymoma or ependymoma subgroups were imported into G-Profiler 22 for pathway analysis, restricted to GO, KEGG and REACTOME gene sets. Cytoscape (v3.2.1) and the EnrichmentMap plug-in was used to generate networks for genesets enriched with an FDR cut-off of < 0.05.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Mack¹,

Pajtler

Chávez

et al. 2017

Nature

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182

218

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SUMMARY Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated based on anatomical location – supratentorial region (ST) or posterior fossa (PF) – and further divided into distinct molecular subgroups that reflect differences in age of onset, gender predominance, and response to therapy1–3. The most common and aggressive subgroup, Posterior Fossa Ependymoma Group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, Posterior Fossa Ependymoma Group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses yet favourable clinical outcomes1,3. Greater than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NFκB subunit RELA (ST-EPN-RELA), and less frequently involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1).1,3,4 Subependymomas, a distinct histologic variant, can also be found within the ST and PF compartments accounting for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE, respectively1. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts with the goal of identifying essential super enhancer associated genes on which tumour cells were dependent. Enhancer regions revealed putative oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, diminished proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.

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Section: Methodsmentioning

confidence: 99%

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Mack¹,

Pajtler

Chávez

et al. 2017

Nature

Self Cite

182

218

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“…To determine features represented by genes with T-DMRs hypomethylated in liver, we applied ontology analysis, using g:GOSt in the g:profiler web database (Table 1; Supplemental Table S2) (Reimand et al 2007). Significantly enriched ontology terms for biological processes (BPs) (P < 10 ‫5מ‬ ) were observed in 1817 g:profiler IDs that had been converted from 2194 Ensembl transcripts with T-DMRs for analysis.…”

Section: Biased Ontology Annotations Of Genes With T-dmrs With Regardmentioning

confidence: 99%

DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression

et al. 2008

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DNA methylation constitutes an important epigenetic regulation mechanism in many eukaryotes, although the extent of DNA methylation in the regulation of gene expression in the mammalian genome is poorly understood. We developed D-REAM, a genome-wide DNA methylation analysis method for tissue-dependent and differentially methylated region (T-DMR) profiling with restriction tag-mediated amplification in mouse tissues and cells. Using a mouse promoter tiling array covering a region from −6 to 2.5 kb (∼30,000 transcription start sites), we found that over 3000 T-DMRs are hypomethylated in liver compared to cerebrum. The DNA methylation profile of liver was distinct from that of kidney and spleen. This hypomethylation profile marked genes that are specifically expressed in liver, including key transcription factors such as Hnf1a and Hnf4a. Genes with T-DMRs, especially those lacking CpG islands and those with HNF-1A binding motifis in their promoters, showed good correlation between their tissue-specific expression and liver hypomethylation status. T-DMRs located downstream from their transcription start sites also showed tissue-specific gene expression. These data indicate that multilayered regulation of tissue-specific gene function could be elucidated by DNA methylation tissue profiling.

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“…A hypergeometric test (with Bonferroni correction for multiple comparisons) was used to select significantly enriched (p < 0.05) terms [64,65]. A log 2 ratio of numbers of each significantly enriched GO term in the test set (phosphoproteins that have Met residues in the vicinity of phosphorylation site) to background set (all phosphoproteins) was calculated.…”

Section: Methodsmentioning

confidence: 99%

Circles within circles: crosstalk between protein Ser/Thr/Tyr-phosphorylation and Met oxidation

Rao

Thelen

et al. 2013

BMC Bioinformatics

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BackgroundReversible posttranslational protein modifications such as phosphorylation of Ser/Thr/Tyr and Met oxidation are critical for both metabolic regulation and cellular signalling. Although these modifications are typically studied individually, herein we describe the potential for cross-talk and hierarchical regulation.ResultsThe proximity of Met to Ser/Thr/Tyr within the proteome has not previously been addressed. In order to consider the possibility of a generalized interaction, we performed a trans-kingdom sequence analysis of known phosphorylation sites in proteins from bacteria, fungi, plants, and animals. The proportion of phosphorylation sites that include a Met within a 13-residue window centered upon Ser/Thr/Tyr is significantly less than the occurrence of Met in proximity to all Ser/Thr/Tyr residues. Met residues are present at all positions (-6 to +6, inclusive) within the 13-residue window that we have considered. Detailed analysis of sequences from eight disparate plant taxa revealed that many conserved phosphorylation sites have a Met residue in the proximity. Results from GO enrichment analysis indicated that the potential for phosphorylation and Met oxidation crosstalk is most prevalent in kinases and proteins involved in signalling.ConclusionThe large proportion of known phosphorylation sites with Met in the proximity fulfils the necessary condition for cross-talk. Kinases/signalling proteins are enriched for Met around phosphorylation sites. These proteins/sites are likely candidates for cross-talk between oxidative signalling and reversible phosphorylation.

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g:Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments

Cited by 1,189 publications

References 26 publications

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

DNA methylation profile of tissue-dependent and differentially methylated regions (T-DMRs) in mouse promoter regions demonstrating tissue-specific gene expression

Circles within circles: crosstalk between protein Ser/Thr/Tyr-phosphorylation and Met oxidation

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