SIGNAL: A web-based iterative analysis platform integrating pathway and network approaches optimizes hit selection from genome-scale assays

Katz, Samuel G.; Song, Jian; Webb, Kyle P.; Lounsbury, Nicolas; Bryant, Clare E.; Fraser, Iain D. C.

doi:10.1016/j.cels.2021.03.001

Cited by 8 publications

(10 citation statements)

References 70 publications

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“…We further examined pathways enriched in differentially expressed genes (DEGs) using the KEGG pathways analysis on the SIGNAL platform (Katz et al, 2021) (Figure 8). Consistent with our data suggesting that DMD astrocytes are in a reactive state, pathways enriched in up‐regulated DEGs were linked to inflammation, such as TNF signaling, cytokine‐cytokine receptor interaction, TGF‐beta signaling and NF‐kappa B signaling (Figure 8a).…”

Section: Resultsmentioning

confidence: 99%

“…Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analysis for Biological Processes was performed using Selection by iterative pathway group and network analysis looping (SIGNAL: https://signal.niaid.nih.gov/) (Katz et al, 2021) in up and down‐regulated genes with p < .05. Log2Fold Changes were used as cut off values (Medium Confidence Cutoff Value >2, High Confidence Cutoff Value >7) and pathways were considered significantly enriched if the FDR was <0.05.…”

Section: Methodsmentioning

confidence: 99%

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Dystrophin deficiency affects human astrocyte properties and response to damage

Lange

Gillham

Alkharji

et al. 2021

Glia

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In addition to progressive muscular degeneration due to dystrophin mutations, 1/3 of Duchenne muscular dystrophy (DMD) patients present cognitive deficits. However, there is currently an incomplete understanding about the function of the multiple dystrophin isoforms in human brains. Here, we tested the hypothesis that dystrophin deficiency affects glial function in DMD and could therefore contribute to neural impairment. We investigated human dystrophin isoform expression with development and differentiation and response to damage in human astrocytes from control and induced pluripotent stem cells from DMD patients. In control cells, short dystrophin isoforms were up-regulated with development and their expression levels changed differently upon neuronal and astrocytic differentiation, as well as in 2-dimensional versus 3-dimensional astrocyte cultures. All DMD-astrocytes tested displayed altered morphology, proliferative activity and AQP4 expression. Furthermore, they did not show any morphological change in response to inflammatory stimuli and their number was significantly lower as compared to stimulated healthy astrocytes. Finally, DMD-astrocytes appeared to be more sensitive than controls to oxidative damage as shown by their increased cell death. Behavioral and metabolic defects in DMD-astrocytes were consistent with gene pathway dysregulation shared by lines with different mutations as demonstrated by bulk RNA-seq analysis.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Dystrophin deficiency affects human astrocyte properties and response to damage

Lange

Gillham

Alkharji

et al. 2021

Glia

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“…For a more detailed analysis of enriched biological processes, we performed enrichment analysis of our transcriptomics and proteomics data sets against KEGG: biological processes database via signal-net analysis without additional fold change filtration (see footnote 2) [accessed 01.02.2022; ( 7 ); Figures 3 , 4 ]. We found a significant shift in VIC physiology in the early stages of osteogenic differentiation associated with the upregulation of many metabolic pathways.…”

Section: Resultsmentioning

confidence: 99%

“…Functional annotation was performed by the DAVID―Database for Annotation, Visualization and Integrated Discovery (v6.8 1 , accessed on 07/02/2022; and by SIGNAL―Selection by Iterative pathway Group and Network Analysis Looping [v1.0 2 ; accessed 07/02/2022; ( 7 )].…”

Section: Methodsmentioning

confidence: 99%

Multi-omics of in vitro aortic valve calcification

Semenova

Zabirnyk²,

Lobov³

et al. 2022

Front. Cardiovasc. Med.

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Heart valve calcification is an active cellular and molecular process that partly remains unknown. Osteogenic differentiation of valve interstitial cells (VIC) is a central mechanism in calcific aortic valve disease (CAVD). Studying mechanisms in CAVD progression is clearly needed. In this study, we compared molecular mechanisms of osteogenic differentiation of human VIC isolated from healthy donors or patients with CAVD by RNA-seq transcriptomics in early timepoint (48 h) and by shotgun proteomics at later timepoint (10th day). Bioinformatic analysis revealed genes and pathways involved in the regulation of VIC osteogenic differentiation. We found a high amount of stage-specific differentially expressed genes and good accordance between transcriptomic and proteomic data. Functional annotation of differentially expressed proteins revealed that osteogenic differentiation of VIC involved many signaling cascades such as: PI3K-Akt, MAPK, Ras, TNF signaling pathways. Wnt, FoxO, and HIF-1 signaling pathways were modulated only at the early timepoint and thus probably involved in the commitment of VIC to osteogenic differentiation. We also observed a significant shift of some metabolic pathways in the early stage of VIC osteogenic differentiation. Lentiviral overexpression of one of the most upregulated genes (ZBTB16, PLZF) increased calcification of VIC after osteogenic stimulation. Analysis with qPCR and shotgun proteomics suggested a proosteogenic role of ZBTB16 in the early stages of osteogenic differentiation.

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“…Therefore, besides removing off-targeting effects, ZetaSuite may also help identify genes that tend to be off-targeted, thereby aiding in siRNA library design similar to GESS [ 70 , 71 ]. We further note that ZetaSuite could be coupled with SIGNAL [ 72 ], an algorithm for prioritizing selected hits according to the information on functional networks and pathways.…”

Section: Discussionmentioning

confidence: 99%

ZetaSuite: computational analysis of two-dimensional high-throughput data from multi-target screens and single-cell transcriptomics

Zhang

Shao

et al. 2022

Genome Biol

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Two-dimensional high-throughput data have become increasingly common in functional genomics studies, which raises new challenges in data analysis. Here, we introduce a new statistic called Zeta, initially developed to identify global splicing regulators from a two-dimensional RNAi screen, a high-throughput screen coupled with high-throughput functional readouts, and ZetaSuite, a software package to facilitate general application of the Zeta statistics. We compare our approach with existing methods using multiple benchmarked datasets and then demonstrate the broad utility of ZetaSuite in processing public data from large-scale cancer dependency screens and single-cell transcriptomics studies to elucidate novel biological insights.

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SIGNAL: A web-based iterative analysis platform integrating pathway and network approaches optimizes hit selection from genome-scale assays

Cited by 8 publications

References 70 publications

Dystrophin deficiency affects human astrocyte properties and response to damage

Dystrophin deficiency affects human astrocyte properties and response to damage

Multi-omics of in vitro aortic valve calcification

ZetaSuite: computational analysis of two-dimensional high-throughput data from multi-target screens and single-cell transcriptomics

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