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Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153658 | GEO | 2020/09/01

REPOSITORIES: GEO

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Multi-omic comparison of Alzheimer's variants in human ESC-derived microglia reveals convergence at APOE.

Project description:Variations in many genes linked to sporadic Alzheimer's disease (AD) show abundant expression in microglia, but relationships among these genes remain largely elusive. Here, we establish isogenic human ESC-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1, and TREM2 loci and curate a comprehensive atlas comprising ATAC-seq, ChIP-seq, RNA-seq, and proteomics datasets. AD-like expression signatures are observed in AD mutant SORL1 and TREM2 hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicates up-regulation of APOE as a convergent pathogenic node. We also observe cross-regulatory relationships between SORL1 and TREM2, in which SORL1R744X hMGLs induce TREM2 expression to enhance APOE expression. AD-associated SORL1 and TREM2 mutations also impaired hMGL Aβ uptake in an APOE-dependent manner in vitro and attenuated Aβ uptake/clearance in mouse AD brain xenotransplants. Using this modeling and analysis platform for human microglia, we provide new insight into epistatic interactions in AD genes and demonstrate convergence of microglial AD genes at the APOE locus.

| S-EPMC7953740 | biostudies-literature

Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE [ChIP-seq]

Project description:Variations in many genes linked to sporadic Alzheimer’s disease (AD), show abundant expression in microglia, however, relationships between these genes remain largely elusive. Here, we establish isogenic human ES-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1 and TREM2 loci, and curate a comprehensive atlas comprising ATACseq, ChIPseq, RNAseq and proteomics datasets. AD-like expression signatures are observed in AD mutant SORL1 and TREM2 hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicates upregulation of APOE as a convergent pathogenic node. We also observe cross-regulatory relationships between SORL1 and TREM2, where SORL1R744X hMGLs induce TREM2 expression to enhance APOE expression. AD-associated SORL1 and TREM2 mutations also impaired hMGL Aβ uptake in an APOE-dependent manner in vitro, and attenuated Aβ uptake/clearance in mouse AD brain xenotransplants. Utilizing this modeling and analysis platform for human microglia, we provide new insight into epistatic interactions in AD genes and demonstrate convergence of microglial AD genes at the APOE locus.

2020-09-01 | GSE153655 | GEO

Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE [ATAC-seq]

2020-09-01 | GSE153654 | GEO

Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE [RNA-seq]

2020-09-01 | GSE153657 | GEO

Multi-omic comparison of Alzheimers variants in human ESC-derived microglia reveals convergence at APOE

Project description:Variations in many genes linked to sporadic Alzheimers disease (AD), show abundant expression in microglia, however, relationships between these genes remain largely elusive. Here, we establish isogenic human ES-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1 and TREM2 loci, and curate a comprehensive atlas comprising ATACseq, ChIPseq, RNAseq and proteomics datasets. AD-like expression signatures are observed in AD mutant SORL1 and TREM2 hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicates upregulation of APOE as a convergent pathogenic node. We also observe cross-regulatory relationships between SORL1 and TREM2, where SORL1R744X hMGLs induce TREM2 expression to enhance APOE expression. AD-associated SORL1 and TREM2 mutations also impaired hMGL A-beta uptake in an APOE-dependent manner in vitro, and attenuated A-beta uptake/clearance in mouse AD brain xenotransplants. Utilizing this modeling and analysis platform for human microglia, we provide new insight into epistatic interactions in AD genes and demonstrate convergence of microglial AD genes at the APOE locus

2020-07-07 | MSV000085698 | MassIVE

Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE

Project description:Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE

| PRJNA643555 | ENA

Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE [ChIP-seq]

Project description:Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE [ChIP-seq]

| PRJNA643558 | ENA

Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE [ATAC-seq]

Project description:Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE [ATAC-seq]

| PRJNA643557 | ENA

Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE [RNA-seq]

Project description:Multi-omic comparison of Alzheimer’s variants in human ESC-derived microglia reveals convergence at APOE [RNA-seq]

| PRJNA643561 | ENA

Multi-omic molecular comparison of primary versus metastatic pancreatic tumours.

Project description:BackgroundMolecular profiling is increasingly used to match patients with metastatic cancer to targeted therapies, but obtaining a high-quality biopsy specimen from metastatic sites can be difficult.MethodsPatient samples were received by Perthera to coordinate genomic, proteomic and/or phosphoproteomic testing, using a specimen from either the primary tumour or a metastatic site. The relative frequencies were compared across specimen sites to assess the potential limitations of using a primary tumour sample for clinical decision support.ResultsNo significant differences were identified at the gene or pathway level when comparing genomic alterations between primary and metastatic lesions. Site-specific trends towards enrichment of MYC amplification in liver lesions, STK11 mutations in lung lesions and ATM and ARID2 mutations in abdominal lesions were seen, but were not statistically significant after false-discovery rate correction. Comparative analyses of proteomic results revealed significantly elevated expression of ERCC1 and TOP1 in metastatic lesions.ConclusionsTumour tissue limitations remain a barrier to precision oncology efforts, and these real-world data suggest that performing molecular testing on a primary tumour specimen could be considered in patients with pancreatic adenocarcinoma who do not have adequate tissue readily available from a metastatic site.

| S-EPMC6738081 | biostudies-literature

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