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The Spatiotemporal Program of DNA Replication Is Associated with Specific Combinations of Chromatin Marks in Human Cells


Replication is the mechanism by which genomes are duplicated into two exact copies. Genomic stability is under the control of a spatiotemporal program that orchestrates both the positioning and the timing of firing of about 50,000 replication starting points, also called replication origins. Replication bubbles found at origins have been very difficult to map due to their short lifespan. Moreover, with the flood of data characterizing new sequencing technologies, the precise statistical analysis of replication data has become an additional challenge. We propose a new method to map replication origins on the human genome, and we assess the reliability of our finding using experimental validation and comparison with origins maps obtained by bubble trapping. This fine mapping then allowed us to identify potential regulators of the replication dynamics. Our study highlights the key role of CpG Islands and identifies new potential epigenetic regulators (methylation of lysine 4 on histone H4, and tri-methylation of lysine 27 on histone H3) whose coupling is correlated with an increase in the efficiency of replication origins, suggesting those marks as potential key regulators of replication. Overall, our study defines new potentially important pathways that might regulate the sequential firing of origins during genome duplication.


Vyšlo v časopise: The Spatiotemporal Program of DNA Replication Is Associated with Specific Combinations of Chromatin Marks in Human Cells. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004282
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004282

Souhrn

Replication is the mechanism by which genomes are duplicated into two exact copies. Genomic stability is under the control of a spatiotemporal program that orchestrates both the positioning and the timing of firing of about 50,000 replication starting points, also called replication origins. Replication bubbles found at origins have been very difficult to map due to their short lifespan. Moreover, with the flood of data characterizing new sequencing technologies, the precise statistical analysis of replication data has become an additional challenge. We propose a new method to map replication origins on the human genome, and we assess the reliability of our finding using experimental validation and comparison with origins maps obtained by bubble trapping. This fine mapping then allowed us to identify potential regulators of the replication dynamics. Our study highlights the key role of CpG Islands and identifies new potential epigenetic regulators (methylation of lysine 4 on histone H4, and tri-methylation of lysine 27 on histone H3) whose coupling is correlated with an increase in the efficiency of replication origins, suggesting those marks as potential key regulators of replication. Overall, our study defines new potentially important pathways that might regulate the sequential firing of origins during genome duplication.


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Štítky
Genetika Reprodukčná medicína

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PLOS Genetics


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