Replication timing predicts long-range chromatin interactions. (A) Profiles of lymphoblastoid replication timing and a model of self-interacting regions of open or closed chromatin (Hi-C–positive values = open; Lieberman-Aiden et al. [2009]). hNPC and hESC replication profiles are shown alongside to illustrate cell-type specificity of the alignment. (B) The correlation between replication timing and the Hi-C chromatin interaction model for each chromosome is shown, calculated as for other epigenetic marks in Figure 4B. (C) Speculative model synthesizing the concepts revealed in Figures 4 and 5. The microscope image is a mouse fibroblast, pulse-labeled with iododeoxyuridine (IdU) early in S phase (green), subsequently pulse-labeled with chlorodeoxyuridine (CldU) late in S phase (red), and then immunofluorescently labeled with antibodies specific to each halogenated nucleotide, as in Wu et al. (2005) and Yokochi et al. (2009). This reveals the spatial compartmentalization of early and late replicating DNA, which is also supported by the reduced frequency of interaction between chromosomal sequences in Hi-C compartments A (green) and B (red). The cartoon is a schematic view of a pair of adjacent early (green) and late replicating (red) domains that are bounded at the early domain side by enrichment of active chromatin marks (yellow star). The replication domains resemble fractal globules described by (Lieberman-Aiden et al. (2009), and late and early domains are spatially separated by a large TTR. Late replicating Hi-C compartment B has a higher frequency of interactions, indicative of more condensed chromatin, which here is proposed to be less accessible to initiation factors for replication than early replicating Hi-C compartment A. (Green and red circles) Different protein components of early vs. late replicating chromatin.
