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Nat Neurosci. 2018 Sep;21(9):1171-1184. doi: 10.1038/s41593-018-0216-z. Epub 2018 Aug 28.

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

Kelley KW1,2,3,4,5, Nakao-Inoue H2,3,4, Molofsky AV2,3,4, Oldham MC6,7,8.

Author information

1
Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA, USA.
2
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA, USA.
3
Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, USA.
4
Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA.
5
Medical Scientist Training Program and Neuroscience Graduate Program, University of California at San Francisco, San Francisco, CA, USA.
6
Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA, USA. Michael.Oldham@ucsf.edu.
7
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA, USA. Michael.Oldham@ucsf.edu.
8
Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, USA. Michael.Oldham@ucsf.edu.

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.

PMID:
30154505
PMCID:
PMC6192711
DOI:
10.1038/s41593-018-0216-z
[Indexed for MEDLINE]
Free PMC Article

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