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

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 and Hagen U. Tilgner ()
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Careen Foord: Weill Cornell Medicine
Andrey D. Prjibelski: University of Helsinki
Wen Hu: Weill Cornell Medicine
Lieke Michielsen: Weill Cornell Medicine
Andrea Vandelli: Istituto Italiano di Tecnologia
Oleksandr Narykov: Worcester Polytechnic Institute
Brian Evans: Weill Cornell Medicine
Justine Hsu: Weill Cornell Medicine
Natan Belchikov: Weill Cornell Medicine
Julien Jarroux: Weill Cornell Medicine
Yi He: Weill Cornell Medicine
M. Elizabeth Ross: Weill Cornell Medicine
Iman Hajirasouliha: Weill Cornell Medicine of Cornell University
Gian Gaetano Tartaglia: Istituto Italiano di Tecnologia
Dmitry Korkin: Worcester Polytechnic Institute
Alexandru I. Tomescu: University of Helsinki
Hagen U. Tilgner: Weill Cornell Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63301-9

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