modEnrichr: a suite of gene set enrichment analysis tools for model organisms

Kuleshov, Maxim V.; Diaz, Jennifer E. L.; Flamholz, Zachary; Keenan, Alexandra B.; Lachmann, Alexander; Wojciechowicz, Megan L.; Cagan, Ross L.; Ma’ayan, Avi

doi:10.1093/nar/gkz347

Cited by 75 publications

(81 citation statements)

References 48 publications

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“…Not only did we find that HCDs were associated with more highly expressed genes than super-enhancers, but we also found that they were associated with genes that are better able to identify erythroid cell types in the Mouse Gene Atlas than genes associated with superenhancers, using Enrichr cell type analysis software 18,19 (Figure 2B, Supplementary File 2).…”

Section: Resultsmentioning

confidence: 78%

“…Microarray expression data for e14.5 fetal liver (maturational stages proerythroblast, basophilic erythroblast, and polychromatic erythroblast) available through ErythronDB (http://www.cbil.upenn.edu/ErythronDB/resources.jsp) were downloaded and used to associate nearby gene expression to domains and non-domains 16,17 . Enrichr (http://amp.pharm.mssm.edu/Enrichr/) was used to perform comprehensive enrichment analysis on associated genes 18,19 .…”

Section: Hcd Analysismentioning

confidence: 99%

“…Super-enhancers were associated with nearby genes using bedtools closest, default settings. Enrichr (http://amp.pharm.mssm.edu/Enrichr/) was used to perform comprehensive enrichment analysis on associated genes 18,19 .…”

Section: Super-enhancer Analysis For the Identification Of Super-enhamentioning

confidence: 99%

“…Enriched cell types were evaluated using Enrichr and the Human Gene Atlas. RNA expression log2(RMA) were downloaded from ArrayExpression (G_GEOD-36984) [18][19][20] .…”

Section: Analysis Of Human Chip-seq and Microarray Data Domains And Smentioning

confidence: 99%

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Hyperacetylated Chromatin Domains Mark Cell Type-Specific Genes and Suggest Distinct Modes of Enhancer Function

Fox

Lillis

Davidson

et al. 2019

Preprint

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Stratification of enhancers by relative signal strength in ChIP-seq assays has resulted in the establishment of super-enhancers as a widespread and useful tool for identifying cell typespecific, highly expressed genes and associated pathways. We have examined a distinct method of stratification that focuses on peak breadth, termed "hyperacetylated chromatin domains" (HCDs), which classifies broad regions exhibiting histone modifications associated with gene activation. We find that this analysis serves to identify genes that are both more highly expressed and more closely aligned to cell identity than super-enhancer analysis does when applied to multiple datasets. Moreover, genetic manipulations of selected gene loci suggest that at least some enhancers located within HCDs work at least in part via a distinct mechanism involving the modulation of covalent histone modifications across domains, and that this activity can be imported into a heterologous gene locus. In addition, such genetic dissection reveals that the super-enhancer concept can obscure important functions of constituent elements. MainEnhancers are cis-regulatory DNA sequences that are bound by transcriptional activators which regulate genetically linked gene promoters 1-5 . They are also historically characterized by their ability to function over distances of anywhere from 100 bp to more than 1 Mb. Whole-genome methods of identifying enhancers rely on associated histone modifications, common transcriptional cofactors, and/or cell type-specific transcription factors (TFs). These methods suggest that mammalian genomes harbor a large number of enhancer sequences -perhaps 1-2 million -and that they represent the most numerous and significant cis-acting sequence determinants of cell type-specific gene expression.Fundamental issues regarding enhancer function, however, remain unclear. For example, there is no consensus for how enhancers communicate with their cognate gene promoters. The dominant model, termed "looping," involves direct interactions between factors bound to enhancers and factors bound near promoters. Evidence for such interactions, however, has provided little insight into how a distal enhancer finds a gene promoter, or how it distinguishes among potential promoters in gene-dense regions. Moreover, some evidence suggests that mechanisms of enhancer-promoter communication may be more varied 3,5 .

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Section: Resultsmentioning

confidence: 78%

Section: Hcd Analysismentioning

confidence: 99%

Section: Super-enhancer Analysis For the Identification Of Super-enhamentioning

confidence: 99%

“…Enriched cell types were evaluated using Enrichr and the Human Gene Atlas. RNA expression log2(RMA) were downloaded from ArrayExpression (G_GEOD-36984) [18][19][20] .…”

Section: Analysis Of Human Chip-seq and Microarray Data Domains And Smentioning

confidence: 99%

See 2 more Smart Citations

Hyperacetylated Chromatin Domains Mark Cell Type-Specific Genes and Suggest Distinct Modes of Enhancer Function

Fox

Lillis

Davidson

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Genes related to diseases, geneto-protein interactions, and protein-protein interaction information can be found in the GenBank 12.21 and String Databases 11.0. We searched signalling pathways related to biomolecules in the Enrichr [11] and Kyoto Encyclopedia of Genes and Genomes (KEGG) . Cytoscape 3.7.1 and systemsdock 4.2.6 were used for network construction and molecular docking respectively.…”

Section: Methodsmentioning

confidence: 99%

Anti-inflammatory Mechanism of Rhein in Treating Asthma Based on Network Pharmacology

Feng

Chen

Wang³

2020

Preprint

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Background: Network pharmacological methods were used to predict the anti-inflammatory targets and related pathways of rhein in the treatment of asthma, and to elucidate its mechanism of action. In addition, we validated the anti-inflammatory effects of rhein in human bronchial epithelial (HBE) cells.Methods: The corresponding targets of rhein were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform 2.3 (TCMSP), and molecular docking was also performed. A network of predicted rhein targets was established and analysed with Cytoscape 3.7.1. The anti-inflammatory targets in the Therapeutic Target Database 2020 (TTD) were searched to build a protein-protein interaction network (PPI), which was merged with the ingredient-target network to screen anti-inflammatory targets associated with rhein. A network of anti-inflammatory rhein targets during the in vivo treatment of asthma was constructed to screen the anti-inflammatory targets related to asthma. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed with the Enrichr database and Cytoscape 3.7.1. The expression levels of proteins in the mitogen-activated protein kinase / nuclear factor kappa-B (MAPK/NF-κB) signalling pathway were assessed by western blot analysis.Results: Altogether, Eighty-three targets were obtained. Epidermal active growth factor receptor (EGFR), E-selecting (E-SELE), macrophage migration inhibitory factor (MIF), and mitogen-activated protein kinase 14 (MAPK14) might be important anti-inflammatory targets of rhein during asthma treatment. We selected the MAPK signalling pathway to determine the anti-inflammatory effects of rhein.Conclusion: The anti-inflammatory mechanism of the treatment of asthma with rhein may be related to MAPK14, EGFR, E-SELE and MIF as well as their signalling pathways. To prevent the exacerbation of asthma, instead of targeting a single pathway or a single target, all these targets and their signalling pathways should be controlled holistically. Rhein may reduce inflammation by inhibiting the MAPK/NF-κB pathway.

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Therapeutic anti‐amyloid β antibodies cause neuronal disturbances

Adhikari

Khan

Mikhael

et al. 2022

Alzheimer's & Dementia

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Recent published clinical trial safety data showed that 41% of Alzheimer patients experienced amyloid-related imaging abnormalities (ARIA), marks of microhemorrhages and oedema in the brain, following administration of Biogen's Aduhelm/ aducanumab (amino acids 3-7 of the Aβ peptide). Similarly, Janssen/Pfizer's Bapineuzumab (amino acids 1-5 of the Aβ peptide) and Roche's Gantenerumab (amino acids 2-11/18-27 of the Aβ peptide) also displayed ARIA in clinical trials, including microhemorrhage and focal areas of inflammation or vasogenic oedema respectively. The molecular mechanisms underlying ARIA caused by therapeutic anti-Aβ antibodies remain largely unknown, however, recent reports demonstrated that therapeutic antiprion antibodies activate both neuronal apoptotic and allergenic proteomes following cross-linking cellular prion protein. Here, we report that treatment of human induced pluripotent stem cellsderived neurons (HSCN) from a non-demented donor, co-cultured with human primary microglia with anti-Aβ1-6, or anti-Aβ17-23 antibodies activate a significant number of both apoptotic and allergenic-related proteins as assessed by mass spectrometry. Interestingly, a large proportion of the identified proteins included cytokines such as IL-4, IL-12, and IL-13 suggesting a type-1 hypersensitivity response. Following flow cytometry analysis, several proinflammatory cytokines were significantly elevated following anti-Aβ1-6, or anti-Aβ17-23 antibody treatment. These results justify further and more robust investigation of the molecular mechanisms of ARIA during immunotherapy study trials of AD.

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modEnrichr: a suite of gene set enrichment analysis tools for model organisms

Cited by 75 publications

References 48 publications

Hyperacetylated Chromatin Domains Mark Cell Type-Specific Genes and Suggest Distinct Modes of Enhancer Function

Hyperacetylated Chromatin Domains Mark Cell Type-Specific Genes and Suggest Distinct Modes of Enhancer Function

Anti-inflammatory Mechanism of Rhein in Treating Asthma Based on Network Pharmacology

Therapeutic anti‐amyloid β antibodies cause neuronal disturbances

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