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Series GSE104381 Query DataSets for GSE104381
Status Public on Jun 29, 2018
Title Loss of Trem2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Rare heterozygous coding variants in the triggering receptor expressed in myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months. Using brain cell-type markers and ontology enrichment, we found subnetworks with cell type and/or functional identity. We primarily discovered changes in an endothelial gene-enriched subnetwork at 4 months, including a shift toward a more central role for the amyloid precursor protein gene, coupled with widespread disruption of other cell-type subnetworks, including a subnetwork with neuronal identity. We reveal an unexpected potential role of Trem2 in the homeostasis of endothelial cells that goes beyond its known functions as a microglial receptor and signaling hub, suggesting an underlying link between immune response and vascular disease in dementia.

Methods: We performed differential expression and co-expression network analysis on a RNA-Seq profiled Trem2 knockout (KO) mouse using two brain areas sampled at 4- and 8-months to obtain a systems level view of the effects of the absence of Trem2.
Results: The absence of Trem2 has a stronger effect at an earlier age with the number of differential expressed (DE) genes being 17-fold greater at 4 months than at 8 months in cortex. By integrating DE genes and network analysis, we discovered gene clusters associated with the disruption of blood vessel formation at 4 months of age and protein targeting primarily affecting the hippocampus at 8 months. Further integration of cell type and ontology information revealed a large disruption of a gene module enriched for endothelial cell markers coinciding with the module enriched for neuron cell markers having weaker connections to modules with oligodendrocyte and astrocyte identities. The module with neuronal identity has decreased expression only in the KO where it has closer association with a new module enriched for phagocytic functions.
Conclusions: Combining gene co-expression and differential expression analysis on a newly generated RNA-Seq profiled Trem2 KO mouse demonstrate that the absence of Trem2 produces a disruption which mainly affects endothelialon related processes at 4 months of age. It results in a ripple effect that disrupts the cross-talk of other cell types at 8 months, including reduced expression of a gene module enriched in neuron related functions and a shift towards a more central role for App. This study reveals an unexpected role of Trem2 in the homeostasis of endothelial cells that goes beyond its known functions as a microglial receptor and signaling hub suggesting new paths for investigation at the intersection between Trem2, Alzheimer’s disease and vascular dementia.
 
Overall design Hippocampus and cortex were selected because they represent tissues affected in AD at early and late stages, respectively (Matarin 2015, Mastrangelo 2008). Brain tissue samples were obtained from male Trem2 knockout (KO) and wild type (WT) control mice at two time points: 4 months and 8 months. These time points span the onset and late disease stages in well established AD mouse models (Matarin 2015). RNA-Seq was used to profile the transcriptomes for each sample. Two technical replicates were obtained for each sample.
Web link https://www.sciencedirect.com/science/article/pii/S0197458018301532
 
Contributor(s) Carbajosa G, Malki K, Lawless N, Wang H, Ryder JW, Wozniak E, Wood K, Mein CA, Dobson RJ, Collier DA, O'Neill MJ, Hodges AK, Newhouse SJ
Citation(s) 29906661
Submission date Sep 28, 2017
Last update date May 15, 2019
Contact name Guillermo Carbajosa
E-mail(s) guillermo.carbajosa_antona@kcl.ac.uk
Phone +44 (0) 207 848 0969
Organization name King's College London
Department Biostatistics & Health Informatics
Lab SGDP Centre, IoPPN, Box PO 80
Street address De Crespigny Park, Denmark Hill
City London
ZIP/Postal code SE5 8AF
Country United Kingdom
 
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (128)
GSM2796628 RD_1-30772751
GSM2796629 RD_1-30974037
GSM2796630 RD_10-30747819
Relations
BioProject PRJNA412500
SRA SRP119064

Download family Format
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Supplementary file Size Download File type/resource
GSE104381_RAW.tar 152.5 Mb (http)(custom) TAR (of TSV)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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