A chromatin structure‐based model accurately predicts DNA replication timing in human cells

Abstract

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.

Behavior of replication origins in Eukaryota – spatio-temporal dynamics of licensing and firing

“…Moreover, biological factors that affect timing mostly do not determine licensing. In accordance with this, we conclude that: (i) empirical analyses of replication in different groups of organisms confirm that mathematical models are accurate for all eukaryotes (plants, animals and even humans, 36 ) and (ii) even the simplest of the mathematical models can be used to determine the probability that a given locus is the site of replication, provided that analysis takes a limited scope of factors affecting replication. Actually, simultaneous analysis of in silico-created data with in vivo-obtained results is also possible to achieve full description of the behavior of replication origins during DNA replication process.…”

“…Gindin et al 36 provide a new interesting mechanical model of predicting DNA replication in human cells. This chromatin structure-based algorithm considers only factors that have an impact on replication timing.…”

Genomic Analysis of the DNA Replication Timing Program during Mitotic S Phase in Maize (Zea mays) Root Tips

“…In maize, we saw a strong association between early replication and published data for MNase HS sites profiled from either root or shoot tissues of 9-d-old maize B73 seedlings (Rodgers-Melnick et al, 2016). This result seems highly significant in light of the fact that in human cells, a simple model of DNA replication produced extremely accurate predictions of replication timing profiles when DNase I HS sites were used to construct a "probability landscape" for initiation (Gindin et al, 2014). Additionally, other studies have noted that DNase I or MNase HS sites are enriched in or near some classes of origins in humans and yeast (Audit et al, 2009;Rodriguez and Tsukiyama, 2013;Mukhopadhyay et al, 2014;Cayrou et al, 2015).…”

Replication timing is regulated by the number of MCMs loaded at origins

“…This mechanism can also naturally explain the observation that slowing the rate of fork progression proportionally slows the rate of origin firing (Alvino et al 2007;Rhind 2008;Koren et al 2010). If a rate limiting factor required for MCM activation travels with the replication fork, such as Cdc45 (Wu and Nurse 2009;Mantiero et al 2011;Tanaka et al 2011;Gindin et al 2014), new origins would be unable to fire until previously initiated forks terminate, coupling origin firing timing to fork progression (Rhind 2008). Another advantage of the multiple-MCM model is that it explains how events that impact origin licensing during G1 can affect the timing of origin firing during S phase.…”

“…Recent results suggest a conceptually similar mechanism may regulate origin timing in human cells (Gindin et al 2014;Rhind 2014). In human cells, the density of DNase I hypersensitive sites is an excellent predictor of replication timing, with regions dense in DNase I hypersensitive sites replicating early (Gindin et al 2014).…”