Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development

Abstract: 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 (www.isoformAtlas.com). 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 (www.isoformAtlas.com). 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.

Anoushka Joglekar, Andrey Prjibelski, Ahmed Mahfouz, Paul Collier, Susan Lin, et al. Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development. BioRxiv, 2020.
@article { bib:2020_brainIso_preprint,
author = { Anoushka Joglekar and Andrey Prjibelski and Ahmed Mahfouz and Paul Collier and Susan Lin and Anna Katharina Schlusche and Jordan Marrocco and Stephen R. Williams and Bettina Haase and Ashley Hayes and Jennifer G. Chew and Neil I Weisenfeld and Man Ying Wong and Alexander N. Stein and Simon Hardwick and Toby Hunt and Zachary Bent and Olivier Fedrigo and Steven A. Sloan and Davide Risso and Erich D. Jarvis and Paul Flicek and Wenjie Luo and Geoffrey S. Pitt and Adam Frankish and August B. Smit and M. Elizabeth Ross and Hagen U. Tilgner },
title = { Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development },
year = { 2020 },
}
brain scISOr-seq screenshot

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