The DOI matches its Crossref record; 107 of the 109 references it cites were found in a registry or an index.
Variation among intact tissue samples reveals the core transcriptional features of human CNS cell classes
Open accessPublished version of a preprint
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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“Other studies have also found that microglial expression, in general, is particularly underrepresented in bulk transcriptomes, relative to that of other brain cell types (8,42) .”
From Single cell transcriptome profiling of the human alcohol-dependent brain (2020) · cites this paper as [42]
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Metadata
- Authors
- Kelley, K. W., Nakao-Inoue, H., Molofsky, A. V., & Oldham, M. C.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Oldham, Michael C.
- Venue
- Nature Neuroscience
- Published
- 2018-08-28
- Volume
- 21
- Issue
- 9
- Pages
- 1171-1184
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6192711
- OpenAlex
- W2951890520
- Cited by
- 198
- References
- 109
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 22 · 2023: 30 · 2022: 26 · 2021: 26 · 2020: 35 · 2019: 29 · 2018: 7
- FWCI
- 8.62
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Sandler Foundation
- University of California, San Francisco
- National Institute of Mental Health (K08MH104417, R01MH113896, DP2MH116507)
- National Institute of General Medical Sciences (T32GM007618)
- Weill Institute for Neurosciences, University of California, San Francisco
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- astrocytes, Alzheimer's disease, regional brain differences, cross-species comparison, gene expression deconvolution, cell identity
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Brain, Central Nervous System, Humans, Models, Genetic, Transcription, Genetic, Sequence Analysis, RNA, Myelin P2 Protein, Gene Expression Profiling, Databases, Genetic, Cell Size, Mice, Transcriptome
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