Long-read RNA sequencing identifies non-coding isoform switching as a regulator of cell fate
10 affiliations
- 1Department of molecular biology, medical biochemistry and pathology, Faculty of Medicine, Université Laval, Quebec City, QC Canada
- 2Oncology Research Program, CHU de Québec-Université Laval Research Centre, Quebec City, QC Canada
- 3Université Laval Cancer Research Centre, Quebec City, QC Canada
- 4Department of Molecular Genetics, University of Toronto, Toronto, ON Canada
- 5Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON Canada
- 6Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC Canada
- 7Department of Human Genetics, McGill University, Montreal, QC Canada
- 8The Centre for Phenogenomics, Toronto, ON Canada
- 9Department of molecular medicine, Faculty of Medicine, Université Laval, Quebec City, QC Canada
- 10Endocrinology and Nephrology Research Program, CHU de Québec-Université Laval Research Centre, Quebec City, QC Canada
Abstract
Development of long-read RNA sequencing technologies has paved the way to the exploration of RNA isoform diversity and its relevance in regulating cell fate. However, identifying new functional isoforms is still very difficult. Here, we leverage long-read RNA sequencing to study changes in isoforms during somatic cell reprogramming and identify novel isoforms occurring throughout cell state transitions. We demonstrate tight regulation of non-coding isoforms and show that isoform switching plays previously overlooked functional roles and outcomes in gene regulation and cell fate changes. We uncover a novel long non-coding RNA, Snhg26, that undergoes isoform switching during reprogramming to enhance the conversion of differentiated cells towards the pluripotent state. Knock-down of Snhg26 in mouse and human pluripotency models reveals that it is important for pluripotency acquisition. Together, our study provides a resource to study full-length isoform usage during cell fate change. It also demonstrates the power of long-read sequencing to identify functionally relevant gene isoforms in the context of cell plasticity.
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BibTeX
@article{fort2026longread,
title = {{Long-read RNA sequencing identifies non-coding isoform switching as a regulator of cell fate}},
author = {Victoire Fort and Gabriel Khelifi and Ruicen He and Valérie Watters and Melanie Pye and Nobuko Yamanaka and Marina Gertsenstein and Émeline I. J. Lelong and Jérémy Loehr and Victoria Micha and Jean-Philippe Lambert and Yojiro Yamanaka and Jeffrey Wrana and Samer M. I. Hussein},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-78011-z},
url = {https://doi.org/10.1038/s41467-026-78011-z},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Long-read RNA sequencing identifies non-coding isoform switching as a regulator of cell fate
AU - Victoire Fort
AU - Gabriel Khelifi
AU - Ruicen He
AU - Valérie Watters
AU - Melanie Pye
AU - Nobuko Yamanaka
AU - Marina Gertsenstein
AU - Émeline I. J. Lelong
AU - Jérémy Loehr
AU - Victoria Micha
AU - Jean-Philippe Lambert
AU - Yojiro Yamanaka
AU - Jeffrey Wrana
AU - Samer M. I. Hussein
PY - 2026
DA - 2026/09/24
JO - Nature Communications
DO - 10.1038/s41467-026-78011-z
UR - https://doi.org/10.1038/s41467-026-78011-z
AB - Development of long-read RNA sequencing technologies has paved the way to the exploration of RNA isoform diversity and its relevance in regulating cell fate. However, identifying new functional isoforms is still very difficult. Here, we leverage long-read RNA sequencing to study changes in isoforms during somatic cell reprogramming and identify novel isoforms occurring throughout cell state transitions. We demonstrate tight regulation of non-coding isoforms and show that isoform switching plays previously overlooked functional roles and outcomes in gene regulation and cell fate changes. We uncover a novel long non-coding RNA, Snhg26, that undergoes isoform switching during reprogramming to enhance the conversion of differentiated cells towards the pluripotent state. Knock-down of Snhg26 in mouse and human pluripotency models reveals that it is important for pluripotency acquisition. Together, our study provides a resource to study full-length isoform usage during cell fate change. It also demonstrates the power of long-read sequencing to identify functionally relevant gene isoforms in the context of cell plasticity.
SN - 2041-1723
ER -