1. Multi-omic comparison of Alzheimer's variants in human ESC-derived microglia reveals convergence at APOE.
- Author
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Liu T, Zhu B, Liu Y, Zhang X, Yin J, Li X, Jiang L, Hodges AP, Rosenthal SB, Zhou L, Yancey J, McQuade A, Blurton-Jones M, Tanzi RE, Huang TY, and Xu H
- Subjects
- Amyloid beta-Peptides metabolism, Animals, Brain pathology, Cell Differentiation, Cell Line, Chromatin metabolism, Epigenesis, Genetic, Gene Regulatory Networks, Gene Targeting, Genetic Loci, Humans, Mice, Transgenic, Models, Biological, Mutant Proteins metabolism, Mutation genetics, Phagocytosis, Proteome metabolism, Signal Transduction, Transcriptome genetics, Transplantation, Heterologous, Up-Regulation genetics, Alzheimer Disease genetics, Alzheimer Disease pathology, Apolipoproteins E genetics, Genetic Variation, Human Embryonic Stem Cells metabolism, Microglia pathology
- Abstract
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., Competing Interests: Disclosures: M. Blurton-Jones reported a patent to WO/2018/160496 licensed "FujiFilm Cellular Dynamics." No other disclosures were reported., (© 2020 Liu et al.)
- Published
- 2020
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