A chromatin structure-based model accurately predicts DNA replication timing in human cells
Article first published online: 28 MAR 2014
© 2014 The Authors. Published under the terms of the CC BY license.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Molecular Systems Biology
Volume 10, Issue 3, March 2014
How to Cite
Mol Syst Biol. (2014) 10: 722
- Issue published online: 28 MAR 2014
- Article first published online: 28 MAR 2014
- Manuscript Accepted: 12 FEB 2014
- Manuscript Revised: 11 FEB 2014
- Manuscript Received: 17 SEP 2013
- NIH. Grant Number: SC1CA1 138180
- National Cancer Institute
- Center for Cancer Research
- computational model;
- DNA replication timing;
- DNase hypersensitivity;
- systems analysis
The metazoan genome is replicated in precise cell lineage-specific temporal order. However, the mechanism controlling this orchestrated process is poorly understood as no molecular mechanisms have been identified that actively regulate the firing sequence of genome replication. Here, we develop a mechanistic model of genome replication capable of predicting, with accuracy rivaling experimental repeats, observed empirical replication timing program in humans. In our model, replication is initiated in an uncoordinated (time-stochastic) manner at well-defined sites. The model contains, in addition to the choice of the genomic landmark that localizes initiation, only a single adjustable parameter of direct biological relevance: the number of replication forks. We find that DNase-hypersensitive sites are optimal and independent determinants of DNA replication initiation. We demonstrate that the DNA replication timing program in human cells is a robust emergent phenomenon that, by its very nature, does not require a regulatory mechanism determining a proper replication initiation firing sequence.
A mechanistic model predicts cell lineage-specific DNA replication timing based on the location of DNase-hypersensitivity data alone. With essentially no parameters to adjust for different cell types, the model is truly predictive even for cells where timing data are not available.
- The mechanistic model predicts replication timing in human cells with an accuracy approaching the limit set by experimental noise.
- In the model, the timing program results from purely time-stochastic initiation at well-localized initiation sites and it is determined by the location of initiation sites alone regardless of initiation probabilities.
- Replication initiation sites are optimally localized by DNase-hypersensitive sites.