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

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

PROVIDER: PRJNA643555 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12129900.fastq.gz	Fastqsanger.gz
	SRR12129906_1.fastq.gz	Fastqsanger.gz
	SRR12129906_2.fastq.gz	Fastqsanger.gz
	SRR12129907_1.fastq.gz	Fastqsanger.gz
	SRR12129907_2.fastq.gz	Fastqsanger.gz

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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.

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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]

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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]

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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]

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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

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

Project description:This SuperSeries is composed of the SubSeries listed below.

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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.

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