Variation among intact tissue samples reveals the core transcriptional features of human CNS cell classes

Nature Neuroscience
Kevin W KelleyMichael C Oldham

Abstract

It is widely assumed that cells must be physically isolated to study their molecular profiles. However, intact tissue samples naturally exhibit variation in cellular composition, which drives covariation of cell-class-specific molecular features. By analyzing transcriptional covariation in 7,221 intact CNS samples from 840 neurotypical individuals, representing billions of cells, we reveal the core transcriptional identities of major CNS cell classes in humans. By modeling intact CNS transcriptomes as a function of variation in cellular composition, we identify cell-class-specific transcriptional differences in Alzheimer's disease, among brain regions, and between species. Among these, we show that PMP2 is expressed by human but not mouse astrocytes and significantly increases mouse astrocyte size upon ectopic expression in vivo, causing them to more closely resemble their human counterparts. Our work is available as an online resource ( http://oldhamlab.ctec.ucsf.edu/ ) and provides a generalizable strategy for determining the core molecular features of cellular identity in intact biological systems.

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Datasets Mentioned

BETA
GSE25219
GSE44770
GSE46706
GSE11882
GSE3790
GSE45642
GSE36192
GSE36980

Methods Mentioned

BETA
fluorescence-activated cell sorting
RNA-seq

Software Mentioned

GEOquery R package
SampleNetwork R
ToppGene
WGCNA
Affymetrix
BLAST
Imaris
tools
STRING
Monocle

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