MAGIC: A tool for predicting transcription factors and cofactors driving gene sets using ENCODE data

As, Roopra

doi:10.1371/journal.pcbi.1007800

Cited by 45 publications

(54 citation statements)

References 43 publications

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“…Thus, the implication of these TFs is consistent with the DEG analysis. A number of bioinformatics tools have been developed to infer differentially expressed TFs from gene expression data (Aibar et al, 2017 ; Madsen et al, 2018 ; Roopra, 2020 ). It will be interesting to see if application of these tools to the scRNA-seq data will reveal similar TFs.…”

mentioning

confidence: 99%

The impact of aging and COVID-19 on our immune system: a high-resolution map from single cell analysis

Yang

2020

Protein Cell

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One key aspect of human aging is the dysregulation of the immune system. As we age, our body's defense system weakens, leading to declined responses to infection by new pathogens and a decreased ability to become immunized (Goronzy and Weyand, 2013; Goronzy and Weyand, 2017). As a result, elderly people are more susceptible to the seasonal flu caused by the constantly mutating influenza viruses. Another manifestation of immune system aging is low grade chronic inflammation, which is linked to many age-related diseases (Glass et al., 2010; Ferrucci and Fabbri, 2018). Recent comprehensive characterization of cellular and molecular changes caused by aging in mammals further revealed the importance of immune system aging, as the up-regulation of genes involved in the inflammatory/immune response turned out to be a highly conserved signature across species and across different organs and tissues (Frenk and Houseley, 2018; Ma et al., 2020; Schaum et al., 2020; Tabula Muris, 2020). In addition, senolytic drugs targeting senescent cells which is a source of chronic inflammation showed great promise in retarding/ preventing many age-related pathologies (Kirkland and Tchkonia, 2020). With the raging COVID-19 pandemic ongoing, the interaction between aging and immune response to the pathogen SARS-CoV-2 has attracted great attention. It has been widely reported that elderly people are more susceptible to COVID-19 and, once infected, the consequence is much more severe. Among the infected, there is a higher rate of admission to ICU and higher rate of death for people aged 65 or older (Onder et al., 2020; Verity et al., 2020). The deaths associated with COVID-19 have been largely attributed to respiratory failure, sepsis, cardiac failure, kidney injury, or coagulopathy. Notably, substantial evidence suggests that in some patients the severity of the outcome is associated with dysregulated and excessive release of cytokines (Laing, 2020; Ye et al., 2020); such overreaction of

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confidence: 99%

The impact of aging and COVID-19 on our immune system: a high-resolution map from single cell analysis

Yang

2020

Protein Cell

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“…Since changes in H3K4me3 do not likely account for Hx-induced gene priming, we used MAGICTRICKS (Roopra, 2019 ) to explore other putative chromatin modifiers that could be associated with Hx-induced gene priming. MAGICTRICKS utilizes a matrix of maximum ChIP-seq scores for every transcription factor at every gene analyzed in the ENCODE database (ENCODE Project Consortium, 2012 ).…”

Section: Resultsmentioning

confidence: 99%

“…Putative transcription factors and cofactors driving gene expression changes were identified using MAGICTRICKS (Roopra, 2019 ). To prepare data for these analyses, we first used the Cuffdiff output to identify genes that were significantly upregulated in Hx LPS relative to Nx LPS (FDR < 5%).…”

Section: Methodsmentioning

confidence: 99%

Prior Hypoxia Exposure Enhances Murine Microglial Inflammatory Gene Expression in vitro Without Concomitant H3K4me3 Enrichment

Kiernan

Ewald

Ouellette

et al. 2020

Front. Cell. Neurosci.

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Hypoxia (Hx) is a component of multiple disorders, including stroke and sleep-disordered breathing, which often precede or are comorbid with neurodegenerative diseases. However, little is known about how hypoxia affects the ability of microglia, resident CNS macrophages, to respond to subsequent inflammatory challenges that are often present during neurodegenerative processes. We, therefore, tested the hypothesis that hypoxia would enhance or “prime” microglial pro-inflammatory gene expression in response to a later inflammatory challenge without programmatically increasing basal levels of pro-inflammatory cytokine expression. To test this, we pre-exposed immortalized N9 and primary microglia to hypoxia (1% O 2 ) for 16 h and then challenged them with pro-inflammatory lipopolysaccharide (LPS) either immediately or 3–6 days following hypoxic exposure. We used RNA sequencing coupled with chromatin immunoprecipitation sequencing to analyze primed microglial inflammatory gene expression and modifications to histone H3 lysine 4 trimethylation (H3K4me3) at the promoters of primed genes. We found that microglia exhibited enhanced responses to LPS 3 days and 6 days post-hypoxia. Surprisingly, however, the majority of primed genes were not enriched for H3K4me3 acutely following hypoxia exposure. Using the bioinformatics tool MAGICTRICKS and reversible pharmacological inhibition, we found that primed genes required the transcriptional activities of NF-κB. These findings provide evidence that hypoxia pre-exposure could lead to persistent and aberrant inflammatory responses in the context of CNS disorders.

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“…Putative transcription factors and cofactors driving gene expression changes were identified using 142 MAGICTRICKS (40). To prepare data for these analyses, we first used the Cuffdiff output to identify 143 genes that were significantly upregulated in Hx LPS relative to Nx LPS (FDR<5%).…”

Section: Magictricks Analyses 141mentioning

confidence: 99%

“…Since changes in H3K4me3 do not likely account for Hx-induced gene priming, we used MAGICTRICKS 292 (40) to explore other putative chromatin modifiers that could be associated with Hx-induced gene 293 priming. MAGICTRICKS utilizes a matrix of maximum ChIP-seq scores for every transcription factor at 294 every gene analyzed in the ENCODE database (48).…”

Section: Magictricks Reveals Multiple Transcription Factors That Putamentioning

confidence: 99%

Prior hypoxia exposure enhances murine microglial inflammatory gene expressionin vitrowithout concomitant H3K4me3 enrichment

Kiernan

Ewald²,

Ouellette³

et al. 2020

Preprint

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31Hypoxia is a component of multiple disorders, including stroke and sleep-disordered breathing, that 32 often precede or are comorbid with neurodegenerative diseases. However, little is known about how 33 hypoxia affects the ability of microglia, resident CNS macrophages, to respond to subsequent 34 inflammatory challenges that are often present during neurodegenerative processes. We therefore 35 tested the hypothesis that hypoxia would enhance or "prime" microglial pro-inflammatory gene 36 expression in response to a later inflammatory challenge without programmatically increasing basal 37 levels of pro-inflammatory cytokine expression. To test this, we pre-exposed immortalized N9 and 38 primary microglia to hypoxia (1% O 2 ) for 16 hrs and then challenged them with pro-inflammatory 39 lipopolysaccharide (LPS) either immediately or 3-6 days following hypoxic exposure. We used RNA 40 sequencing coupled with chromatin immunoprecipitation sequencing to analyze primed microglial 41 inflammatory gene expression and modifications to histone H3 lysine 4 trimethylation (H3K4me3) at the 42 promoters of primed genes. We found that microglia exhibited enhanced responses to LPS 3 days and 6 43 days post-hypoxia. Surprisingly however, the majority of primed genes were not enriched for H3K4me3 44 acutely following hypoxia exposure. Using the bioinformatics tool MAGICTRICKS and reversible 45 pharmacological inhibition, we found that primed genes required the transcriptional activities of NF-ĸB. 46These findings provide evidence that hypoxia pre-exposure could lead to persistent and aberrant 47 inflammatory responses in the context of CNS disorders. 48 49 memory 51 52 17% of women aged 30-70, characterized by recurrent bouts of Hx during sleep (6). This disorder causes 57 long-term cognitive deficits (7-11) and increases susceptibility to multiple neurodegenerative diseases 58 (12)(13)(14)(15)(16). Despite the common co-occurrence of Hx with neural disease, few studies have investigated 59 how pre-exposure to Hx changes the long-term ability of resident CNS macrophages/microglia to 60 respond to a subsequent inflammatory insult, such as pathogen exposure or a sterile inflammatory 61 stimulus. 62In peripheral and CNS immune cells, there is significant cross-talk between the pathways mediating 63 responses to Hx and inflammation (reviewed in (17, 18)), including shared activation of the transcription 64 factor HIF-1α (19), suggesting a mechanism whereby Hx could have long-term effects on microglial 65 inflammatory responses. In normoxia (Nx), pathogen exposure activates HIF-1α and shifts peripheral 66 macrophage metabolism from oxidative phosphorylation to glycolysis, promoting a more pro-67 inflammatory M1 phenotype (20)(21)(22). This metabolic shift "primes" peripheral macrophages and 68 enhances their pro-inflammatory cytokine expression upon subsequent pathogen exposure, even long 69 after the initial pathogen stimulus has been removed (20)(21)(22). Although the ability of Hx-induced HIF-1α 70 to similarly prime macrophage/m...

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MAGIC: A tool for predicting transcription factors and cofactors driving gene sets using ENCODE data

Cited by 45 publications

References 43 publications

The impact of aging and COVID-19 on our immune system: a high-resolution map from single cell analysis

The impact of aging and COVID-19 on our immune system: a high-resolution map from single cell analysis

Prior Hypoxia Exposure Enhances Murine Microglial Inflammatory Gene Expression in vitro Without Concomitant H3K4me3 Enrichment

Prior hypoxia exposure enhances murine microglial inflammatory gene expressionin vitrowithout concomitant H3K4me3 enrichment

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