Enrichr-KG: bridging enrichment analysis across multiple libraries

Evangelista, John Erol; Xie, Zhuorui; Marino, Giacomo B; Nguyen, Nhi; Clarke, Daniel J B; Ma’ayan, Avi

doi:10.1093/nar/gkad393

Cited by 36 publications

(31 citation statements)

References 106 publications

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“…We performed integrative functional enrichment analysis using Enrichr Knowledge Graph (Enrichr-KG) to identify associations between DEGs and mammalian phenotypes and biological processes. 41 Using this unbiased approach, we identified important gene-phenotype associations between Nkx2-5, Pitx2, Sema3c, Pcsk6/Pace4, and Lama5 and the conotruncal defects, DORV and PTA. Mutant mouse models of each of these genes have been reported to exhibit DORV and PTA.…”

Section: Nkx2-5 Enhancer Regulates a Critical Oft Transcriptomementioning

confidence: 99%

An Anterior Second Heart Field Enhancer Regulates the Gene Regulatory Network of the Cardiac Outflow Tract

Yamaguchi,

Chang,

Lin

et al. 2023

Circulation

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BACKGROUND: Conotruncal defects due to developmental abnormalities of the outflow tract (OFT) are an important cause of cyanotic congenital heart disease. Dysregulation of transcriptional programs tuned by NKX2-5, GATA6, and TBX1 have been implicated in abnormal OFT morphogenesis. However, there remains no consensus on how these transcriptional programs function in a unified gene regulatory network within the OFT. METHODS: We generated mice harboring a 226-nucleotide deletion of a highly conserved cardiac enhancer containing 2 GATA-binding sites located ≈9.4 kb upstream of the transcriptional start site of Nkx2-5 ( Nkx2-5 ∆enh ) using CRISPR-Cas9 gene editing and assessed phenotypes. Cardiac defects in Nkx2-5 ∆enh/∆enh mice were structurally characterized using histology and scanning electron micrography, and physiologically assessed using electrocardiography, echocardiography, and optical mapping. Transcriptome analyses were performed using RNA sequencing and single-cell RNA sequencing data sets. Endogenous GATA6 interaction with and activity on the NKX2-5 enhancer was studied using chromatin immunoprecipitation sequencing and transposase-accessible chromatin sequencing in human induced pluripotent stem cell–derived cardiomyocytes. RESULTS: Nkx2-5 ∆enh/∆enh mice recapitulated cyanotic conotruncal defects seen in patients with NKX2-5, GATA6, and TBX1 mutations. Nkx2-5 ∆enh/∆enh mice also exhibited defects in right Purkinje fiber network formation, resulting in right bundle-branch block. Enhancer deletion reduced embryonic Nkx2-5 expression selectively in the right ventricle and OFT of mutant hearts, indicating that enhancer activity is localized to the anterior second heart field. Transcriptional profiling of the mutant OFT revealed downregulation of important genes involved in OFT rotation and septation, such as Tbx1, Pitx2, and Sema3c . Endogenous GATA6 interacted with the highly conserved enhancer in human induced pluripotent stem cell–derived cardiomyocytes and in wild-type mouse hearts. We found critical dose dependency of cardiac enhancer accessibility on GATA6 gene dosage in human induced pluripotent stem cell–derived cardiomyocytes. CONCLUSIONS: Our results using human and mouse models reveal an essential gene regulatory network of the OFT that requires an anterior second heart field enhancer to link GATA6 with NKX2-5–dependent rotation and septation gene programs.

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Section: Nkx2-5 Enhancer Regulates a Critical Oft Transcriptomementioning

confidence: 99%

An Anterior Second Heart Field Enhancer Regulates the Gene Regulatory Network of the Cardiac Outflow Tract

Yamaguchi,

Chang,

Lin

et al. 2023

Circulation

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“…We identified a cluster, Cluster 6 (IC6), that was associated with proteinuria, comprising 253 genes. Using Enrichr-KG, we identified several interaction nodes through Gene Ontology (GO): Biological Function and the KEGG 2021 pathways, including Epithelial Development, ECM-Receptor Interaction, Skin Development, Keratinocyte Differentiation, PI3K-Akt Signaling Pathway, Estrogen Signaling Pathway, Negative Regulation of Signaling, Staphylococcus aureus Infection, and IL-17 Signaling (Figure S2) (30). This pattern of gene expression and interactions suggests that in Col4α3-/mice, processes such as renal epithelial cell growth, matrix remodeling, and cell adhesion are more active compared to WT mice and are associated with proteinuria.…”

Section: Results (2360 Words)mentioning

confidence: 99%

Glomerular Elasticity and Gene Expression Patterns Define Two Phases of Alport Nephropathy

Yoon,

Liu,

Alaba

et al. 2024

Preprint

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Rationale: Mutations in COL4A3,4, or 5 cause Alport syndrome and contribute to other glomerular diseases. Potential mechanisms include abnormal GBM structure, chemistry, elasticity, or ER stress. The causes of initial podocyte injury are not fully defined in collagen IV nephropathies. Objectives: We characterized renal function, structural and biophysical properties of glomerular capillaries and podocytes, and renal gene expression patterns in Col4a3 KO mice (BL6) over the 8-month course of disease. To test for a role for ER stress, we treated Col4a3 KO mice with TUDCA. Findings: Col4a3 KO mice develop proteinuria and reduced renal function at 4 to 5 months, but their glomerular capillaries become abnormally deformable, and podocytes are dislodged into the urine with volume loading at 3 months. Glomeruli become maximally deformable at 4 months with loss of 40% of their podocytes, and then stiffen progressively with progression of renal disease. In parallel, kidneys become increasingly fibrotic with proteinuria and inflammatory infiltrates as renal failure progresses. Bulk renal gene expression changes from 2 and 4 months where it shows increased expression of genes related to matrix organization, cytokine signaling, and cell injury to reduction in genes coding for differentiated renal tubular and metabolic proteins. Treatment of mice with TUDCA minimized glomerular injury, loss of renal function, and increased expression of genes that inhibit MAP, tyrosine kinase, and TGF Beta. Conclusion: Renal disease in Col4a3 KO mice progresses in two phases, before overt proteinuria with early podocyte injury and loss, and later with overt proteinuria and progressive fibrosis. Suppression of renal injury by TUDCA implicates ER stress and MAP, tyrosine kinase, and TGF-B signaling as a disease mechanism.

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“…The specific genes of interest were identified in terms of statistical significance (adjusted p-value < 0.05) and substantial differential expression between groups. The differentially expressed genes (DEGs) obtained from the comparisons were then subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis using the enrich-KEGG (35) function from the R package cluster Profiler (36) with default parameters. Gene ontology (G.O.)…”

Section: Methodsmentioning

confidence: 99%

Profiling plasma extracellular vesicle-derived microRNAs for noninvasive diagnosis of alpha-1 antitrypsin deficiency associated liver disease

Oshins,

Huo,

Poole

et al. 2023

Preprint

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Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease characterized by reduced circulating levels of alpha-1 antitrypsin (AAT) due to the retention of misfolded AAT in the hepatocytes. The toxic AAT aggregates in hepatocytes cause liver fibrosis, cirrhosis, and hepatocellular carcinoma. Most patients remain asymptomatic until the final stage in which liver transplantation becomes the only treatment. Timely diagnosis of AATD liver disease plays a critical role in intervention and finding curative solutions. Assessing the prevalence and severity of AATD liver disease remains challenging due to limitations in current methods. Liver biopsy, the gold standard for evaluating the hepatic AAT accumulation, the initiating stage for AATD liver disease, is hindered by invasiveness and sampling errors. To address these limitations, we conducted a study using unique and precious clinical samples. We analyzed plasma extracellular vesicle (EV) derived miRNAs and liver transcriptomes from AATD individuals to develop a sensitive and noninvasive diagnostic approach for AATD liver disease. In the testing stage of our study, we enrolled 17 AATD individuals with different stages of liver disease, as determined by liver biopsy, and 20 controls. We identified differential expression of 178 miRNAs within the AATD group compared to controls by miRNA sequencing. Among those miRNAs, we selected miR-223-3p, miR-23a-3p, miR-15b-5p, let-7a-5p, let-7f-5p, and miR-374a-5p for further validation in an independent cohort of 45 AATD individuals. Using a logistic model that combined three miRNAs, we achieved an AUC of 0.737 for detecting AATD liver disease. Adding a fourth miRNA into this model increased the AUC to 0.751. The changes in EV miRNAs are correlated to dysregulated expression of liver mRNAs in AATD individuals with different stages of liver disease. We propose that plasma-circulating EV exhibit distinct miRNAs in AATD individuals and could serve as clinically significant biomarkers for the early detection of AATD liver disease.

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Enrichr-KG: bridging enrichment analysis across multiple libraries

Cited by 36 publications

References 106 publications

An Anterior Second Heart Field Enhancer Regulates the Gene Regulatory Network of the Cardiac Outflow Tract

An Anterior Second Heart Field Enhancer Regulates the Gene Regulatory Network of the Cardiac Outflow Tract

Glomerular Elasticity and Gene Expression Patterns Define Two Phases of Alport Nephropathy

Profiling plasma extracellular vesicle-derived microRNAs for noninvasive diagnosis of alpha-1 antitrypsin deficiency associated liver disease

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