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<p>Genome-wide spatial long-read approaches often lack single-cell resolution and yield limited read lengths. Here, we introduce spatial ISOform sequencing (Spl-ISO-Seq), which reveals exons and polyadenylation sites with near-single-cell resolution. Spl-ISO-Seq selects long cDNAs and doubles to triples read lengths compared to standard preparations. Adding a highly specific software tool (Spl-ISOquant) and comparing human post-mortem pre-puberty (8–11 years) to post-puberty (16–19 years) visual cortex samples, we find that cortex harbors stronger splicing and poly(A)-site regulation than white matter. However, oligodendrocyte regulation is stronger in white matter. Among cortical layers, layer 4 has the most developmentally-regulated splicing changes in excitatory neurons and in poly(A) sites. We also find repeat elements downstream of developmentally-regulated layer 4 exons. Overall, alternative splicing changes are linked to post-synaptic structure and function. These results root developmental splicing changes during puberty in specific layers and cell types. More generally, our technologies enable exciting observations for any complex tissue.</p>

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A spatial long-read approach at near-single-cell resolution reveals developmental regulation of splicing and polyadenylation sites in distinct cortical layers and cell types

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月29日

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  • Careen Foord,
  • Andrey D. Prjibelski,
  • Wen Hu,
  • Lieke Michielsen,
  • Andrea Vandelli,
  • Oleksandr Narykov,
  • Brian Evans,
  • Justine Hsu,
  • Natan Belchikov,
  • Julien Jarroux,
  • Yi He,
  • M. Elizabeth Ross,
  • Iman Hajirasouliha,
  • Gian Gaetano Tartaglia,
  • Dmitry Korkin,
  • Alexandru I. Tomescu,
  • Hagen U. Tilgner

摘要

Genome-wide spatial long-read approaches often lack single-cell resolution and yield limited read lengths. Here, we introduce spatial ISOform sequencing (Spl-ISO-Seq), which reveals exons and polyadenylation sites with near-single-cell resolution. Spl-ISO-Seq selects long cDNAs and doubles to triples read lengths compared to standard preparations. Adding a highly specific software tool (Spl-ISOquant) and comparing human post-mortem pre-puberty (8–11 years) to post-puberty (16–19 years) visual cortex samples, we find that cortex harbors stronger splicing and poly(A)-site regulation than white matter. However, oligodendrocyte regulation is stronger in white matter. Among cortical layers, layer 4 has the most developmentally-regulated splicing changes in excitatory neurons and in poly(A) sites. We also find repeat elements downstream of developmentally-regulated layer 4 exons. Overall, alternative splicing changes are linked to post-synaptic structure and function. These results root developmental splicing changes during puberty in specific layers and cell types. More generally, our technologies enable exciting observations for any complex tissue.