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High Resolution Repli-Seq defines the temporal choreography of initiation, elongation and termination of replication in mammalian cells

Peiyao A. Zhao, Takayo Sasaki, View ORCID ProfileDavid M. Gilbert
doi: https://doi.org/10.1101/755629
Peiyao A. Zhao
Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, FL 32306, USA
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Takayo Sasaki
Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, FL 32306, USA
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David M. Gilbert
Department of Biological Science, 319 Stadium Drive, Florida State University, Tallahassee, FL 32306, USA
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  • ORCID record for David M. Gilbert
  • For correspondence: gilbert@bio.fsu.edu
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ABSTRACT

DNA replication in mammalian cells occurs in a defined temporal order during S phase, known as the replication timing (RT) programme. RT is developmentally regulated and correlated with chromatin conformation and local transcriptional potential. Here we present RT profiles of unprecedented temporal resolution in two human embryonic stem cell lines, human colon carcinoma line HCT116 as well as F1 subspecies hybrid mouse embryonic stem cells and their neural progenitor derivatives. Strong enrichment of nascent DNA in fine temporal windows reveals a remarkable degree of cell to cell conservation in replication timing and patterns of replication genome-wide. We identify 5 patterns of replication in all cell types, consistent with varying degrees of initiation efficiency. Zones of replication initiation were found throughout S phase and resolved to ~50kb precision. Temporal transition regions were resolved into segments of uni-directional replication punctuated with small zones of inefficient initiation. Small and large valleys of convergent replication were consistent with either termination or broadly distributed initiation, respectively. RT correlated with chromatin compartment across all cell types but correlations of initiation time to chromatin domain boundaries and histone marks were cell type specific. Haplotype phasing revealed previously unappreciated regions of allele-specific and alleleindependent asynchronous replication. Allele-independent asynchrony was associated with large transcribed genes that resemble common fragile sites. Altogether, these data reveal a remarkably deterministic temporal choreography of DNA replication in mammalian cells.

  • Highly homogeneous replication landscape between cells in a population

  • Initiation zones resolved within constant timing and timing transition regions

  • Active histone marks enriched within early initiation zones while enrichment of repressive marks is cell type specific.

  • Transcribed long genes replicate asynchronously.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 05, 2019.
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High Resolution Repli-Seq defines the temporal choreography of initiation, elongation and termination of replication in mammalian cells
Peiyao A. Zhao, Takayo Sasaki, David M. Gilbert
bioRxiv 755629; doi: https://doi.org/10.1101/755629
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High Resolution Repli-Seq defines the temporal choreography of initiation, elongation and termination of replication in mammalian cells
Peiyao A. Zhao, Takayo Sasaki, David M. Gilbert
bioRxiv 755629; doi: https://doi.org/10.1101/755629

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