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Transcription elongation can be sufficient, but is not necessary, to advance replication timing

ABSTRACT: DNA replication timing (RT) is correlated with transcription during cell fate changes but there are many exceptions, underscoring a need for reductionist approaches. Here, we manipulated length and strength of transcription at a single site upstream of the silent, late-replicating, Pleiotrophin (Ptn) gene in mouse embryonic stem cells (mESCs). Reporter genes driven by two of four promoters elicited an RT advance while all four promoters advanced RT when driving the endogenous Ptn gene. Inducible transcription of the Ptn gene, but not the reporter gene, elicited a rapid and reversible RT advance. Deletion of the Ptn promoter and enhancer, followed by differentiation to neural precursors, eliminated transcription without attenuating the natural Ptn domain RT advance. Together with new genome-wide analyses, our results provide a solid empirical base with which to re-evaluate many decades of seemingly contradictory literature. We also identify vectors that do not disturb RT and provide a robust system to induce RT changes, permitting mechanistic studies of transcription’s role in RT and the consequences of RT changes to epigenomic remodeling.

ORGANISM(S): Mus musculus

PROVIDER: GSE310676 | GEO | 2026/02/01

REPOSITORIES: GEO

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Transcription elongation can be sufficient, but is not necessary, to advance replication timing [Repli-seq]

Project description:DNA replication timing (RT) is correlated with transcription during cell fate changes but there are many exceptions, underscoring a need for reductionist approaches. Here, we manipulated length and strength of transcription at a single site upstream of the silent, late-replicating, Pleiotrophin (Ptn) gene in mouse embryonic stem cells (mESCs). Reporter genes driven by two of four promoters elicited an RT advance while all four promoters advanced RT when driving the endogenous Ptn gene. Inducible transcription of the Ptn gene, but not the reporter gene, elicited a rapid and reversible RT advance. Deletion of the Ptn promoter and enhancer, followed by differentiation to neural precursors, eliminated transcription without attenuating the natural Ptn domain RT advance. Together with new genome-wide analyses, our results provide a solid empirical base with which to re-evaluate many decades of seemingly contradictory literature. We also identify vectors that do not disturb RT and provide a robust system to induce RT changes, permitting mechanistic studies of transcription’s role in RT and the consequences of RT changes to epigenomic remodeling.

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Transcription elongation can be sufficient, but is not necessary, to advance replication timing

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