Dataset Information

Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Data.

ABSTRACT: Establishing the molecular diversity of cell types is crucial for the study of the nervous system. We compiled a cross-laboratory database of mouse brain cell type-specific transcriptomes from 36 major cell types from across the mammalian brain using rigorously curated published data from pooled cell type microarray and single-cell RNA-sequencing (RNA-seq) studies. We used these data to identify cell type-specific marker genes, discovering a substantial number of novel markers, many of which we validated using computational and experimental approaches. We further demonstrate that summarized expression of marker gene sets (MGSs) in bulk tissue data can be used to estimate the relative cell type abundance across samples. To facilitate use of this expanding resource, we provide a user-friendly web interface at www.neuroexpresso.org.

SUBMITTER: Mancarci BO

PROVIDER: S-EPMC5707795 | biostudies-literature | 2017 Nov-Dec

REPOSITORIES: biostudies-literature

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Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Data.

Mancarci B Ogan BO Toker Lilah L Tripathy Shreejoy J SJ Li Brenna B Rocco Brad B Sibille Etienne E Pavlidis Paul P

eNeuro 20171130 6

Establishing the molecular diversity of cell types is crucial for the study of the nervous system. We compiled a cross-laboratory database of mouse brain cell type-specific transcriptomes from 36 major cell types from across the mammalian brain using rigorously curated published data from pooled cell type microarray and single-cell RNA-sequencing (RNA-seq) studies. We used these data to identify cell type-specific marker genes, discovering a substantial number of novel markers, many of which we ...[more]

PMID: 29204516

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Project description:BackgroundVariation in cell composition can dramatically impact analyses in bulk tissue samples. A commonly employed approach to mitigate this issue is to adjust statistical models using estimates of cell abundance derived directly from omics data. While an arsenal of estimation methods exists, the applicability of these methods to brain tissue data and whether or not cell estimates can sufficiently account for confounding cellular composition has not been adequately assessed.MethodsWe assessed the correspondence between different estimation methods based on transcriptomic (RNA sequencing, RNA-seq) and epigenomic (DNA methylation and histone acetylation) data from brain tissue samples of 49 individuals. We further evaluated the impact of different estimation approaches on the analysis of H3K27 acetylation chromatin immunoprecipitation sequencing (ChIP-seq) data from entorhinal cortex of individuals with Alzheimer's disease and controls.ResultsWe show that even closely adjacent tissue samples from the same Brodmann area vary greatly in their cell composition. Comparison across different estimation methods indicates that while different estimation methods applied to the same data produce highly similar outcomes, there is a surprisingly low concordance between estimates based on different omics data modalities. Alarmingly, we show that cell type estimates may not always sufficiently account for confounding variation in cell composition.ConclusionsOur work indicates that cell composition estimation or direct quantification in one tissue sample should not be used as a proxy to the cellular composition of another tissue sample from the same brain region of an individual-even if the samples are directly adjacent. The highly similar outcomes observed among vastly different estimation methods, highlight the need for brain benchmark datasets and better validation approaches. Finally, unless validated through complementary experiments, the interpretation of analyses outcomes based on data confounded by cell composition should be done with great caution, and ideally avoided all together.

Dataset Information

Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Data.

Publications

Cross-Laboratory Analysis of Brain Cell Type Transcriptomes with Applications to Interpretation of Bulk Tissue Data.

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