Gene Set Knowledge Discovery with Enrichr

Xie, Zhuorui; Bailey, Allison; Kuleshov, Maxim V.; Clarke, Daniel J B; Evangelista, John Erol; Jenkins, Sherry L.; Lachmann, Alexander; Wojciechowicz, Megan L.; Kropiwnicki, Eryk; Jagodnik, Kathleen M.; Jeon, Minji; Ma’ayan, Avi

doi:10.1002/cpz1.90

Cited by 1,950 publications

(1,681 citation statements)

References 34 publications

Supporting

Mentioning

1,447

Contrasting

Order By: Relevance

“…Annotation based enrichment was performed using two sided Fisher exact tests, which was done through LOLA (v1.20.0) for the chromatin state enrichments (Sheffield and Bock 2015), and the odds ratios were converted to fold enrichments for data visualization. enrichR (v3.0) was used for gene symbol based GO, PANTHER pathway, and GEO RNA-seq disease and drug signature enrichment testing (Chen et al 2013; Jawaid 2021; Kuleshov et al 2016; Xie et al 2021). regioneR (v1.22.0) was utilized to perform permutation based genomic coordinate enrichment testing through a randomized region strategy with 10,000 permutations (Gel et al 2016).…”

Section: Methodsmentioning

confidence: 99%

Genome-Wide DNA Methylation Profiles of Neurodevelopmental Disorder Genes in Mouse Placenta and Fetal Brain Following Prenatal Exposure to Polychlorinated Biphenyls

Laufer

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Polychlorinated biphenyls (PCBs) are developmental neurotoxicants implicated as environmental risk factors for neurodevelopmental disorders (NDD), including autism spectrum disorders (ASD). Objective: We examined the effects of prenatal exposure to a human-relevant mixture of PCBs on the DNA methylome of fetal mouse brain and placenta to determine if there was a shared subset of differentially methylated regions (DMRs). Methods: A PCB mixture formulated to model the 12 most abundant congeners detected in the serum of pregnant women from a prospective high-risk ASD cohort was administered to female mice prior to and during pregnancy. Whole-genome bisulfite sequencing (WGBS) was performed to assess genome-wide DNA methylation profiles of placenta and brain on gestational day 18. Results: We found thousands of significant (empirical p < 0.05) DMRs distinguishing placentas and brains from PCB-exposed embryos from sex-matched vehicle controls. In both placenta and brain, PCB-associated DMRs were significantly (p < 0.005) enriched for functions related to neurodevelopment, cellular adhesion, and cellular signaling, and significantly (Odds Ratio > 2.4, q < 0.003) enriched for bivalent chromatin marks. The placenta and brain PCB DMRs overlapped significantly (Z-score = 4.5, p = 0.0001) by genomic coordinate and mapped to a shared subset of genes significantly (q < 0.05) enriched for Wnt signaling, Slit/Robo signaling, and genes differentially expressed in multiple NDD/ASD models. The placenta and brain DMRs also significantly (q < 0.05) overlapped by genomic coordinate with brain samples from humans with Rett syndrome and Dup15q syndrome. Discussion: These results demonstrate that placenta can be used as a surrogate for embryonic brain DNA methylation changes over genes relevant to NDD/ASD in a mouse model of prenatal PCB exposure.

show abstract

Section: Methodsmentioning

confidence: 99%

Genome-Wide DNA Methylation Profiles of Neurodevelopmental Disorder Genes in Mouse Placenta and Fetal Brain Following Prenatal Exposure to Polychlorinated Biphenyls

Laufer

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Transcriptional regulatory relationships unraveled by sentence-based text mining (TRRUST), a bioinformatics tool provided through the TRRUST website ( www.grnpedia.org/trrust ; [ 40 ]), was used to show transcription factors associated with our gene lists of interest, using a cut-off of 1.5 for the total fold change. KEGG pathway analysis was performed on gene sets of interest using the EnrichR database ( https://maayanlab.cloud/Enrichr/# , [ 41 ]). The Venn diagram is based on differentially expressed gene lists for each LPS-stimulus condition for the BV2 shCtrl and sh Atg7 , respectively.…”

Section: Methodsmentioning

confidence: 99%

Atg7 deficiency in microglia drives an altered transcriptomic profile associated with an impaired neuroinflammatory response

et al. 2021

View full text Add to dashboard Cite

Microglia, resident immunocompetent cells of the central nervous system, can display a range of reaction states and thereby exhibit distinct biological functions across development, adulthood and under disease conditions. Distinct gene expression profiles are reported to define each of these microglial reaction states. Hence, the identification of modulators of selective microglial transcriptomic signature, which have the potential to regulate unique microglial function has gained interest. Here, we report the identification of ATG7 (Autophagy-related 7) as a selective modulator of an NF-κB-dependent transcriptional program controlling the pro-inflammatory response of microglia. We also uncover that microglial Atg7-deficiency was associated with reduced microglia-mediated neurotoxicity, and thus a loss of biological function associated with the pro-inflammatory microglial reactive state. Further, we show that Atg7-deficiency in microglia did not impact on their ability to respond to alternative stimulus, such as one driving them towards an anti-inflammatory/tumor supportive phenotype. The identification of distinct regulators, such as Atg7, controlling specific microglial transcriptional programs could lead to developing novel therapeutic strategies aiming to manipulate selected microglial phenotypes, instead of the whole microglial population with is associated with several pitfalls.

show abstract

“…SE and MXE, AS event types focused on in this work, composed approximately 50% and 20% of all AS events, respectively. Gene ontology (GO) analysis was performed to reveal enriched functional pathways affected by significant gene expression changes as well as alternative splicing changes using EnrichR (Chen et al, 2013; Kuleshov et al, 2016; Xie et al, 2021). The top enriched GO terms with smallest adjusted p values were visualized as bar plots.…”

Section: Methodsmentioning

confidence: 99%

Alternative splicing regulates the physiological adaptation of the mouse hind limb postural and phasic muscles to microgravity

Henrich¹,

P²,

Js³

et al. 2021

Preprint

View full text Add to dashboard Cite

Muscle atrophy and fiber type alterations are well-characterized physiological adaptations to microgravity with both understood to be primarily regulated by differential gene expression (DGE). While microgravity-induced DGE has been extensively investigated, adaptations to microgravity due to alternative splicing (AS) have not been studied in a mammalian model. We sought to comprehensively elucidate the transcriptomic underpinnings of microgravity-induced muscle phenotypes in mice by evaluating both DGE and changes in AS due to extended spaceflight. Tissue sections and total RNA were isolated from the gastrocnemius and quadriceps, postural and phasic muscles of the hind limb, respectively, of 32-week-old female BALB/c mice exposed to microgravity or ground control conditions for nine weeks. Immunohistochemistry disclosed muscle type-specific physiological adaptations to microgravity that included i) a pronounced reduction in muscle fiber cross-sectional area in both muscles and ii) a prominent slow-to-fast fiber type transition in the gastrocnemius. RNA sequencing revealed that DGE and AS varied across postural and phasic muscle types with preferential employment of DGE in the gastrocnemius and AS in the quadriceps. Gene ontology analysis indicated that DGE and AS regulate distinct molecular processes. Various non-differentially expressed transcripts encoding musculoskeletal proteins (Tnnt3, Tnnt1, Neb, Ryr1, and Ttn) and muscle-specific RNA binding splicing regulators (Mbnl1 and Rbfox1) were found to have significant changes in AS that altered critical functional domains of their protein products. In striking contrast, microgravity-induced differentially expressed genes were associated with lipid metabolism and mitochondrial function. Our work serves as the first comprehensive investigation of coordinate changes in DGE and AS in large limb muscles across spaceflight. We propose that substantial remodeling of pre-mRNA by AS is a major component of transcriptomic adaptation of skeletal muscle to microgravity. The alternatively spliced genes identified here could be targeted by small molecule splicing regulator therapies to address microgravity-induced changes in muscle during spaceflight.

show abstract

Gene Set Knowledge Discovery with Enrichr

Cited by 1,950 publications

References 34 publications

Genome-Wide DNA Methylation Profiles of Neurodevelopmental Disorder Genes in Mouse Placenta and Fetal Brain Following Prenatal Exposure to Polychlorinated Biphenyls

Genome-Wide DNA Methylation Profiles of Neurodevelopmental Disorder Genes in Mouse Placenta and Fetal Brain Following Prenatal Exposure to Polychlorinated Biphenyls

Atg7 deficiency in microglia drives an altered transcriptomic profile associated with an impaired neuroinflammatory response

Alternative splicing regulates the physiological adaptation of the mouse hind limb postural and phasic muscles to microgravity

Contact Info

Product

Resources

About