Single-cell splice isoform usage reveals distinct axes of cellular identity and senescence
- 1Stanford University
Abstract
Alternative splicing greatly expands the diversity of gene products encoded by the human genome. Single-cell transcriptomic atlases have characterized human cell types through gene-level expression, but short-read sequencing has limited the ability to resolve full-length isoforms and their functional consequences. Here, we present a cross-tissue single-cell long-read isoform atlas spanning 26 human tissues. We identify hundreds of thousands of novel isoforms along with their cell-type-specific usage, and discover that over one-third of expressed isoforms are absent from existing reference databases. We further demonstrate that isoform usage is a structured, measurable axis of cellular identity that is distinct from gene expression. Applying this framework to cellular senescence, we resolve p16INK4a and p14ARF transcripts from the CDKN2A locus in individual cells and uncover cell-type-dependent isoform remodeling associated with the p16INK4a senescence program. This isoform-resolved single-cell atlas offers a versatile framework to dissect the cellular logic of isoform regulation in senescence and beyond.
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BibTeX
@misc{mantri2026singlecell,
title = {{Single-cell splice isoform usage reveals distinct axes of cellular identity and senescence}},
author = {M. Mantri and A. M. Detweiler and J. Lee and J. H.-Y. Kwon and A. Zhou and L. Tong and R. C. Jones and N. F. Neff and Tabula Sapiens Consortium and S. R. Quake},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.748700},
url = {https://www.biorxiv.org/content/10.64898/2026.09.11.748700v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Single-cell splice isoform usage reveals distinct axes of cellular identity and senescence
AU - M. Mantri
AU - A. M. Detweiler
AU - J. Lee
AU - J. H.-Y. Kwon
AU - A. Zhou
AU - L. Tong
AU - R. C. Jones
AU - N. F. Neff
AU - Tabula Sapiens Consortium
AU - S. R. Quake
PY - 2026
DA - 2026/09/11
PB - bioRxiv
DO - 10.64898/2026.09.11.748700
UR - https://www.biorxiv.org/content/10.64898/2026.09.11.748700v1
AB - Alternative splicing greatly expands the diversity of gene products encoded by the human genome. Single-cell transcriptomic atlases have characterized human cell types through gene-level expression, but short-read sequencing has limited the ability to resolve full-length isoforms and their functional consequences. Here, we present a cross-tissue single-cell long-read isoform atlas spanning 26 human tissues. We identify hundreds of thousands of novel isoforms along with their cell-type-specific usage, and discover that over one-third of expressed isoforms are absent from existing reference databases. We further demonstrate that isoform usage is a structured, measurable axis of cellular identity that is distinct from gene expression. Applying this framework to cellular senescence, we resolve p16INK4a and p14ARF transcripts from the CDKN2A locus in individual cells and uncover cell-type-dependent isoform remodeling associated with the p16INK4a senescence program. This isoform-resolved single-cell atlas offers a versatile framework to dissect the cellular logic of isoform regulation in senescence and beyond.
ER -