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Spatio-temporal organization of replication: On genome evolution and large-scale chromatin folding

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Taking advantage of the recent availability of high resolution timing data, we show for seven human cell types that about half of the genome is divided in megabase-sized domains that display a characteristic Ushaped replication timing profile with early initiation zones at borders and late replication at centers. Significant overlap is observed between U-domains of different cell types and also with germline replication domains exhibiting a N-shaped nucleotide compositional skew confirming that the putative origins at Ndomains borders are likely to be active in different cell lines. 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. When investigating further the large scale organization of human genes with respect to replication, we show that the replication origins at U/N-domain borders, gene orientation and gene expression are not randomly distributed but on the opposite are at the heart of a strong organization of human chromosomes. In particular highly expressed genes in a given cell type are over-represented close to the corresponding replication U/N-domain borders. When mapping experimental and numerical chromatin mark data in replication U/N-domains, we find, surrounding most of the putative replication origins that replicate early in the S phase, regions of a few hundred kbp wide that are hypersensitive to DNase cleavage, that are hypomethylated and that present a significant enrichment in epigenetic marks of open and transcriptionally active chromatin. Analysis of chromatin interaction (Hi-C) data further reveals that replication domains actually correspond to high-order chromatin structural units that likely contribute to the compartmentalization of the genome into autonomous domains of gene transcription and replication. We propose a cascade model for replication where replication of N/U-domains preferentially initiates at master replication origins located at their open chromatin borders and that secondary origins within each domain subsequently fire stimulated by approaching forks from earlier-activated origins.

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