Replication Fork Polarity Gradients Revealed by Megabase-Sized U-Shaped Replication Timing Domains in Human Cell Lines

Université de Lyon, Lyon, France.
PLoS Computational Biology (Impact Factor: 4.62). 04/2012; 8(4):e1002443. DOI: 10.1371/journal.pcbi.1002443
Source: PubMed


In higher eukaryotes, replication program specification in different cell types remains to be fully understood. We show for seven human cell lines that about half of the genome is divided in domains that display a characteristic U-shaped replication timing profile with early initiation zones at borders and late replication at centers. Significant overlap is observed between U-domains of different cell lines and also with germline replication domains exhibiting a N-shaped nucleotide compositional skew. From the demonstration that the average fork polarity is directly reflected by both the compositional skew and the derivative of the replication timing profile, we argue that the fact that this derivative displays a N-shape in U-domains sustains the existence of large-scale gradients of replication fork polarity in somatic and germline cells. Analysis of chromatin interaction (Hi-C) and chromatin marker data reveals that U-domains correspond to high-order chromatin structural units. We discuss possible models for replication origin activation within U/N-domains. The compartmentalization of the genome into replication U/N-domains provides new insights on the organization of the replication program in the human genome.

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    • "To ensure that this estimation is robust, we recalculated FP from RT at distances ranging between 0.5 and 15 kb from the current coordinate; all resulting values were strongly correlated (Spearman's ρ > 0.995). Absolute values of RT change reflect the propensity of FP toward unidirectionality (Baker et al. 2012). We divided the genome into nine bins according to the values of FP: eight bins each containing 10% of all nucleotides, and one bin centered at FP = 0, containing 20% of all nucleotides. "
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    • "Hundreds of megabase-sized domains with a U-shaped timing profile were identified independent of skew analysis (Baker et al., 2012; Audit et al., 2013). Demonstrating that the timing gradient equaled the ratio of fork speed to fork directionality led us to predict an N-shaped fork directionality profile of U domains strikingly similar to skew N domains (Guilbaud et al., 2011; Baker et al., 2012). U domains coincided with chromatin modification seems too abundant (80% of all H4 molecules) to explain origin specificity (Schotta et al., 2008). "
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