A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain
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Abstract
Splicing varies across brain regions, but the single-cell resolution of regional variation is unclear. We present a single-cell investigation of differential isoform expression (DIE) between brain regions using single-cell long-read sequencing in mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7 ( www.isoformAtlas.com ). Isoform tests for DIE show better performance than exon tests. We detect hundreds of DIE events traceable to cell types, often corresponding to functionally distinct protein isoforms. Mostly, one cell type is responsible for brain-region specific DIE. However, for fewer genes, multiple cell types influence DIE. Thus, regional identity can, although rarely, override cell-type specificity. Cell types indigenous to one anatomic structure display distinctive DIE, e.g. the choroid plexus epithelium manifests distinct transcription-start-site usage. Spatial transcriptomics and long-read sequencing yield a spatially resolved splicing map. Our methods quantify isoform expression with cell-type and spatial resolution and it contributes to further our understanding of how the brain integrates molecular and cellular complexity.
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Using long-read scRNA-seq data from the mouse hippocampus, hdWGCNA uncovered splicing isoform co-expression networks in the radial glia lineage involved in cell fate specification.
“Using long-read scRNA-seq data from the mouse hippocampus,8 we uncovered splicing isoform co-expression networks in the radial glia lineage involved in cell fate specification.”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [8]
hdWGCNA performed isoform co-expression network analysis in radial glia lineage cells from the mouse hippocampus at postnatal day 7 profiled with single-cell isoform RNA sequencing (ScISOrSeq).
“We used hdWGCNA to perform isoform co-expression network analysis in radial glia lineage cells from the mouse hippocampus at postnatal day 7 (P7) profiled with single-cell isoform RNA sequencing (ScISOrSeq)8 (Figure 4A; STAR Methods).”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [8]
Emerging long-read sequencing approaches enable profiling cellular transcriptomes at isoform resolution.
“Emerging long-read sequencing approaches enable us to profile cellular transcriptomes at isoform resolution,8,31,32,33 thus providing new opportunities to model the relationships between isoforms using co-expression network analysis.”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [8]
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- Authors
- Joglekar, A., Prjibelski, A., Mahfouz, A., Collier, P., Lin, S., Schlusche, A. K., Marrocco, J., Williams, S. R., Haase, B., Hayes, A., Chew, J. G., Weisenfeld, N. I., Wong, M. Y., Stein, A. N., Hardwick, S. A., Hunt, T., Wang, Q., Dieterich, C., Bent, Z., Fedrigo, O., Sloan, S. A., Risso, D., Jarvis, E. D., Flicek, P., Luo, W., Pitt, G. S., Frankish, A., Smit, A. B., Ross, M. E., & Tilgner, H. U.
- Affiliations
- Weill Cornell Medicine (US)
- St Petersburg University (RU)
- Leiden University Medical Center (NL)
- Rockefeller University (US)
- 10X Genomics (United States) (US)
- Columbia University (US)
- Garvan Institute of Medical Research (AU)
- European Bioinformatics Institute (GB)
- University Hospital Heidelberg (DE)
- Emory University (US)
- University of Padua (IT)
- Howard Hughes Medical Institute (US)
- Amsterdam Neuroscience (NL)
- Corresponding author
- Tilgner, Hagen U.
- ORCID
- Joglekar, Anoushka
- Prjibelski, Andrey
- Mahfouz, Ahmed
- Lin, Susan
- Schlusche, Anna Katharina
- Marrocco, Jordan
- Williams, Stephen R.
- Haase, Bettina
- Wong, Man Ying
- Stein, Alexander N.
- Hardwick, Simon A.
- Hunt, Toby
- Wang, Qi
- Dieterich, Christoph
- Fedrigo, Olivier
- Sloan, Steven A.
- Risso, Davide
- Jarvis, Erich D.
- Flicek, Paul
- Luo, Wenjie
- Pitt, Geoffrey S.
- Frankish, Adam
- Smit, August B.
- Ross, M. Elizabeth
- Tilgner, Hagen U.
- Venue
- Nature Communications
- Published
- 2021-01-19
- Volume
- 12
- Issue
- 1
- Pages
- 463-463
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7815907
- OpenAlex
- W3122762933
- Cited by
- 229
- References
- 94
- Citations by year
- 2026: 22 · 2025: 39 · 2024: 52 · 2023: 45 · 2022: 30 · 2021: 39 · 2020: 1 · 2018: 1
- FWCI
- 13.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Research Repository (Delft University of Technology) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Russian Foundation for Basic Research (19-04-01074)
- U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (T32DA03980)
- Silicon Valley Community Foundation (CZF2019-002443)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (2U24CA180996)
- Wellcome Trust (WT108749/Z/15/Z)
- U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (2U41HG007234)
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH118934)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- differential isoform expression, alternative splicing, brain region specificity, cell type specificity, hippocampus, prefrontal cortex, postnatal mouse brain, spatial transcriptomics, choroid plexus epithelium
- MeSH terms
- Animals, Animals, Newborn, Female, Hippocampus, Prefrontal Cortex, Alternative Splicing, Gene Expression Regulation, Developmental, Computational Biology, Protein Isoforms, Models, Animal, Mice, Single-Cell Analysis, Spatial Analysis
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