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Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways.

ABSTRACT: Because mouse models play a crucial role in biomedical research related to the human nervous system, understanding the similarities and differences between mouse and human brain is of fundamental importance. Studies comparing transcription in human and mouse have come to varied conclusions, in part because of their relatively small sample sizes or underpowered methodologies. To better characterize gene expression differences between mouse and human, we took a systems-biology approach by using weighted gene coexpression network analysis on more than 1,000 microarrays from brain. We find that global network properties of the brain transcriptome are highly preserved between species. Furthermore, all modules of highly coexpressed genes identified in mouse were identified in human, with those related to conserved cellular functions showing the strongest between-species preservation. Modules corresponding to glial and neuronal cells were sufficiently preserved between mouse and human to permit identification of cross species cell-class marker genes. We also identify several robust human-specific modules, including one strongly correlated with measures of Alzheimer disease progression across multiple data sets, whose hubs are poorly-characterized genes likely involved in Alzheimer disease. We present multiple lines of evidence suggesting links between neurodegenerative disease and glial cell types in human, including human-specific correlation of presenilin-1 with oligodendrocyte markers, and significant enrichment for known neurodegenerative disease genes in microglial modules. Together, this work identifies convergent and divergent pathways in mouse and human, and provides a systematic framework that will be useful for understanding the applicability of mouse models for human brain disorders.

SUBMITTER: Miller JA

PROVIDER: S-EPMC2906579 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways.

Miller Jeremy A JA Horvath Steve S Geschwind Daniel H DH

Proceedings of the National Academy of Sciences of the United States of America 20100625 28

Because mouse models play a crucial role in biomedical research related to the human nervous system, understanding the similarities and differences between mouse and human brain is of fundamental importance. Studies comparing transcription in human and mouse have come to varied conclusions, in part because of their relatively small sample sizes or underpowered methodologies. To better characterize gene expression differences between mouse and human, we took a systems-biology approach by using we ...[more]

PMID: 20616000

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Project description:BackgroundWhile Alzheimer disease (AD) is generally considered as a brain disorder, blood biomarkers may be useful for the diagnosis and prediction of AD brain pathology. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood-brain barrier (BBB) breakdown.MethodsWe evaluated the differential expression of previously established AD genes in brains from 344 pathologically confirmed AD cases and 232 controls and in blood from 112 pathologically confirmed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. Differential gene expression between AD cases and controls was analyzed in the blood and brain jointly using a multivariate approach in the total sample and within APOE genotype groups. Gene set enrichment analysis was performed within APOE genotype groups using the results from the combined blood and brain analyses to identify biologically important pathways. Gene co-expression networks in brain and blood samples were investigated using weighted correlation network analysis. Top-ranked genes from networks and pathways were further evaluated with vascular injury traits.ResultsWe observed differentially expressed genes with P < 0.05 in both brain and blood for established AD genes INPP5D (upregulated) and HLA-DQA1 (downregulated). PIGHP1 and FRAS1 were differentially expressed at the transcriptome-wide level (P < 3.3 × 10-6) within ε2/ε3 and ε3/ε4 groups, respectively. Gene set enrichment analysis revealed 21 significant pathways (false discovery rate P < 0.05) in at least one APOE genotype group. Ten pathways were significantly enriched in the ε3/ε4 group, and six of these were unique to these subjects. Four pathways (allograft rejection, interferon gamma response, peroxisome, and TNFA signaling via NFKB) were enriched for AD upregulated genes in the ε3/ε4 group and AD downregulated genes in subjects lacking ε4. We identified a co-expressed gene network in the brain that reproduced in blood and showed higher average expression in ε4 carriers. Twenty-three genes from pathway and network analyses were significantly associated with at least one vascular injury trait.ConclusionThese results suggest that the APOE genotype contributes to unique expression network profiles in both blood and brain. Several genes in these networks are associated with measures of vascular injury and potentially contribute to ε4's effect on the BBB.

Project description:PurposeThe purpose of this study was to analyze the transcriptomic changes in the striatum of amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and uncover its association with the methyl-CpG binding protein 2 (MeCP2) mediated-changes in striatal epigenetic signature during Alzheimer disease (AD) pathological progression.MethodsTo observe transcriptomic alterations in the striatum before the onset of cognitive impairment in APP/PS1 mice, quantitative 3'mRNA sequencing was performed with RNA extracted from the striatum of 6-month-old and 12-month-old wildtype and APP/PS1 mice. In addition, chromatin immunoprecipitation sequencing was conducted with the DNA from wildtype and APP/PS1 mice of the same age as aforementioned. For transcriptomic analysis, comparison terms were constructed based on aging and transgene expression-normal-aging (12-month-old wildtype/6-month-old wildtype), early-AD (6-month-old APP/PS1/6-month-old wildtype), and late-AD (12-month-old APP/PS1/6-month-old wildtype). To compare the changes in biological pathways and networks, we analyzed gene lists from each comparison term via bioinformatics tools including DAVID (Database for Annotation, Visualization, and Integrated Discovery), STRING (Search Tool for the Retrieval of Interacting Genes/Proteins), and SynGO (Synaptic Gene Ontologies). Furthermore, to assume the effect MeCP2 in AD pathological conditions may have on the transcriptome regulation, analysis of the common genes from Quant-Seq and MeCP2-ChIP-Seq was performed.ResultsEnriched pathways including immune system and inflammatory response were confirmed in normal- aging and lateAD, respectively. In particular, enriched pathways of gene expression regulation, transcriptional regulation, and protein catabolic pathways were found to be significantly altered in early-AD. MeCP2-bound genes that were significantly altered in the transcriptome were suggested to be target genes that have a role in the striatum of the early-stage AD model.ConclusionThis study confirmed that the alteration of the striatal transcriptomic profile in APP/PS1 mice was involved with several biological pathways. Additionally, comparative analysis of the transcriptomic changes and the MeCP2 bound regions found that a group of differentially expressed genes may be regulated under the epigenetic control of MeCP2.

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Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways.

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Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways.

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