Slow RNAPII elongation enhances naive pluripotency rewiring while maintaining high replication fork speed

DNA replication and transcription must be intricately coordinated as both machineries navigate the same chromatin landscape to ensure genome stability and proper cell function. Here, we show that altering their elongation rates-specifically, slowed transcriptional elongation alongside rapid replication fork progression-does not elicit replicative stress. Instead, this independent kinetic variation accelerates the acquisition of naive pluripotency during in vitro dedifferentiation, revealing an unexpected link between transcription kinetics and cell plasticity. Mechanistically, we show that the transition to naive pluripotency is accompanied by a distinctive alternative splicing program indicative of reduced RNA polymerase II (RNAPII) elongation. These findings redefine the functional relationship between replication and transcription dynamics and uncover transcriptional velocity as a tunable layer of control over cellular identity transitions.

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Publication Details

Journal
Science Advances
Published
2026-04-24
DOI
https://doi.org/10.1126/sciadv.adz6211
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
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article

Slow RNAPII elongation enhances naive pluripotency rewiring while maintaining high replication fork speed

Andrei Chabes, Biswajit Das, Magdalena M. Maslon, Jesús Rafael Rodríguez‐Aguilera et al.
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article

Slow RNAPII elongation enhances naive pluripotency rewiring while maintaining high replication fork speed

Andrei Chabes, Biswajit Das, Magdalena M. Maslon, Jesús Rafael Rodríguez‐Aguilera, Sara Martín-Vírgala, Ran Tong, Javier Isoler‐Alcaráz, Joana Segura, Sara Tur-Gracia, Alicia Gallego, Lothar Schermelleh, María Gómez, Shraddha Shinde, Carlos Gallego-García
article en

Abstract

DNA replication and transcription must be intricately coordinated as both machineries navigate the same chromatin landscape to ensure genome stability and proper cell function. Here, we show that altering their elongation rates-specifically, slowed transcriptional elongation alongside rapid replication fork progression-does not elicit replicative stress. Instead, this independent kinetic variation accelerates the acquisition of naive pluripotency during in vitro dedifferentiation, revealing an unexpected link between transcription kinetics and cell plasticity. Mechanistically, we show that the transition to naive pluripotency is accompanied by a distinctive alternative splicing program indicative of reduced RNA polymerase II (RNAPII) elongation. These findings redefine the functional relationship between replication and transcription dynamics and uncover transcriptional velocity as a tunable layer of control over cellular identity transitions.

Science AdvancesVol. 12(17)
Jagiellonian University (PL), University of Oxford (GB), Centro de Biología Molecular Severo Ochoa (ES), Universidad Autónoma de Madrid (ES), Umeå University (SE)
Openalex Percentile: Top 8%
Genomics and Chromatin Dynamics
DOIOpen Access PDFOpenAlex
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