A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain

Anoushka Joglekar, Andrey Prjibelski, Ahmed Mahfouz, Paul Collier, Susan Lin, Anna Katharina Schlusche, Jordan Marrocco, Stephen R. Williams, Bettina Haase, Ashley Hayes, Jennifer G. Chew, Neil I. Weisenfeld, Man Ying Wong, Alexander N. Stein, Simon A. Hardwick, Toby Hunt, Qi Wang, Christoph Dieterich, Zachary Bent, Olivier Fedrigo, Steven A. Sloan, Davide Risso, Erich D. Jarvis, Paul Flicek, Wenjie Luo, Geoffrey S. Pitt, Adam Frankish, August B. Smit, M. Elizabeth Ross and Hagen U. Tilgner ()
Additional contact information
Anoushka Joglekar: Weill Cornell Medicine
Andrey Prjibelski: St. Petersburg State University
Ahmed Mahfouz: Leiden University Medical Center
Paul Collier: Weill Cornell Medicine
Susan Lin: Weill Cornell Medical College
Anna Katharina Schlusche: Weill Cornell Medicine
Jordan Marrocco: The Rockefeller University
Stephen R. Williams: 10x Genomics
Bettina Haase: The Rockefeller University
Ashley Hayes: 10x Genomics
Jennifer G. Chew: 10x Genomics
Neil I. Weisenfeld: 10x Genomics
Man Ying Wong: Weill Cornell Medicine
Alexander N. Stein: Columbia University
Simon A. Hardwick: Weill Cornell Medicine
Toby Hunt: European Bioinformatics Institute
Qi Wang: University Hospital
Christoph Dieterich: University Hospital
Zachary Bent: 10x Genomics
Olivier Fedrigo: The Rockefeller University
Steven A. Sloan: Emory University School of Medicine
Davide Risso: University of Padova
Erich D. Jarvis: The Rockefeller University
Paul Flicek: European Bioinformatics Institute
Wenjie Luo: Weill Cornell Medicine
Geoffrey S. Pitt: Weill Cornell Medical College
Adam Frankish: European Bioinformatics Institute
August B. Smit: VU University
M. Elizabeth Ross: Weill Cornell Medicine
Hagen U. Tilgner: Weill Cornell Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20343-5

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