Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development
By
Anoushka Joglekar,
Andrey D Przhibelskiy,
Ahmed Mahfouz,
Paul Collier,
Susan Lin,
Anna K Schlusche,
Jordan Marrocco,
Stephen R. Williams,
Bettina Haase,
Ashley Hayes,
Jennifer G Chew,
Neil I Weisenfeld,
Man Ying Wong,
Alexander N Stein,
Simon Hardwick,
Toby Hunt,
Zachary Bent,
Olivier Fedrigo,
Steven A. Sloan,
Davide Risso,
Erich J Jarvis,
Paul Flicek,
Wenjie Luo,
Geoffrey S Pitt,
Adam Frankish,
August B Smit,
Margaret Elizabeth Ross,
Hagen Tilgner
Posted 27 Aug 2020
bioRxiv DOI: 10.1101/2020.08.27.268730
Alternative RNA splicing varies across brain regions, but the single-cell resolution of such regional variation is unknown. Here we present the first single-cell investigation of differential isoform expression (DIE) between brain regions, by performing single cell long-read transcriptome sequencing in the mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7. Using isoform tests for brain-region specific DIE, which outperform exon-based tests, we detect hundreds of brain-region specific DIE events traceable to specific cell-types. Many DIE events correspond to functionally distinct protein isoforms, some with just a 6-nucleotide exon variant. In most instances, one cell type is responsible for brain-region specific DIE. Cell types indigenous to only one anatomic structure display distinctive DIE, where for example, the choroid plexus epithelium manifest unique transcription start sites. However, for some genes, multiple cell-types are responsible for DIE in bulk data, indicating that regional identity can, although less frequently, override cell-type specificity. We validated our findings with spatial transcriptomics and long-read sequencing, yielding the first spatially resolved splicing map in the postnatal mouse brain. Our methods are highly generalizable. They provide a robust means of quantifying isoform expression with cell-type and spatial resolution, and reveal how the brain integrates molecular and cellular complexity to serve function. ### Competing Interest Statement The authors have declared no competing interest.
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