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

Area of Science:

• Cellular dynamics
• Molecular biology
• Epigenetics

Background:

• DNA replication and transcription are crucial for genome stability.
• Coordination between these processes is essential for proper cell function.
• Their interplay within the chromatin landscape is complex.

Purpose of the Study:

• To investigate the impact of altered DNA replication and transcription elongation rates on cellular processes.
• To explore the relationship between transcription kinetics and cell plasticity.
• To uncover mechanisms linking transcriptional velocity to cellular identity transitions.

Main Methods:

• Manipulating elongation rates of DNA replication and transcription in vitro.
• Analyzing the effects of kinetic variations on replicative stress.
• Investigating alternative splicing programs during cell dedifferentiation.
• Measuring RNA polymerase II (RNAPII) elongation rates.

Main Results:

• Slower transcriptional elongation with faster replication did not induce replicative stress.
• This independent kinetic variation accelerated the acquisition of naive pluripotency.
• A distinct alternative splicing program, indicating reduced RNAPII elongation, accompanied the transition to naive pluripotency.

Conclusions:

• The functional relationship between replication and transcription dynamics is redefined.
• Transcriptional velocity emerges as a controllable factor in cellular identity transitions.
• Cell plasticity is unexpectedly linked to transcription kinetics.