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Locally-correlated kinetics of post-replication DNA methylation reveals processivity and region-specificity in DNA methylation maintenance

Honglei Ren, Robert B. Taylor, Timothy L. Downing, Elizabeth L. Read
doi: https://doi.org/10.1101/2021.09.28.462223
Honglei Ren
1NSF-Simons Center for Multiscale Cell Fate, University of California, Irvine, CA, USA
2Center for Complex Biological Systems, University of California, Irvine, California, USA
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Robert B. Taylor
2Center for Complex Biological Systems, University of California, Irvine, California, USA
3Dept. of Physics, University of California, Irvine, California, USA
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Timothy L. Downing
1NSF-Simons Center for Multiscale Cell Fate, University of California, Irvine, CA, USA
2Center for Complex Biological Systems, University of California, Irvine, California, USA
4Dept. of Biomedical Engineering, University of California, Irvine, California, USA
5Dept. of Microbiology & Molecular Genetics, University of California, Irvine, California, USA
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  • For correspondence: tldownin@uci.edu elread@uci.edu
Elizabeth L. Read
1NSF-Simons Center for Multiscale Cell Fate, University of California, Irvine, CA, USA
2Center for Complex Biological Systems, University of California, Irvine, California, USA
6Dept. of Chemical & Biomolecular Engineering, University of California, Irvine, CA, USA
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  • For correspondence: tldownin@uci.edu elread@uci.edu
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Abstract

DNA methylation occurs predominantly on cytosine-phosphate-guanine (CpG) dinucleotides in the mammalian genome, and the methylation landscape is maintained over mitotic cell division. It has been posited that coupling of methylation activity among neighboring CpGs is critical to collective stability over cellular generations, however the mechanism of this coupling is unclear. We used mathematical models and stochastic simulation to analyze data from experiments that probe genome-wide methylation of nascent DNA post-replication. We find that DNA methylation maintenance shows genomic-region-specific kinetics, indicating influence of local CpG density and chromatin accessibility on methyltransferase activity and inter-CpG coupling. We uncover evidence of processive methylation kinetics in post-replication DNA, which manifests as exponential decay of methylation rate correlation on neighboring CpGs. Our results indicate that processivity is a component of inter-CpG-coupling that occurs globally throughout the genome, but other mechanisms of coupling dominate for inter-CpG distances past 100 basepairs. By decomposing local methylation correlations into processive and non-processive components, we estimate that an individual methyltransferase methylates neighbor CpGs in sequence if they are 36 basepairs apart, on average. Our study demonstrates that detailed information on epigenomic dynamics can be gleaned from replication-associated, cell-based genome-wide measurements, by combining data-driven statistical analyses with hypothesis-driven mathematical modeling.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 28, 2021.
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Locally-correlated kinetics of post-replication DNA methylation reveals processivity and region-specificity in DNA methylation maintenance
Honglei Ren, Robert B. Taylor, Timothy L. Downing, Elizabeth L. Read
bioRxiv 2021.09.28.462223; doi: https://doi.org/10.1101/2021.09.28.462223
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Locally-correlated kinetics of post-replication DNA methylation reveals processivity and region-specificity in DNA methylation maintenance
Honglei Ren, Robert B. Taylor, Timothy L. Downing, Elizabeth L. Read
bioRxiv 2021.09.28.462223; doi: https://doi.org/10.1101/2021.09.28.462223

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