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: 4.83). 04/2012; 8(4):e1002443. DOI: 10.1371/journal.pcbi.1002443
Source: PubMed

ABSTRACT 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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    ABSTRACT: We review the existence of a new type of megabase-sized replication domains along the human genome. These domains are revealed in 7 somatic cell types by U-shaped patterns in the replication timing profiles. In the germline, these domains appear as N-shaped patterns in the DNA compositional asymmetry profiles resulting from replication-associated mutational asymmetries. We demonstrated that the average replication fork polarity is directly proportional to both the DNA compositional asymmetry and the derivative of the replication timing profile. Hence, the average fork polarity changes in a linear manner across U/N-replication domains enlightening a robust mode of replication across cell types and during evolution. Using genome-wide chromatin conformation data, we found that the replication domains remarkably coincide with self-interacting folding units of the chromatin fiber and that their borders are long-range interconnected hubs in the chromatin interaction graph. Altogether our results suggest that the spatio-temporal replication program is intimately coupled to a high-order 3D organization of the human genome.

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