Developmental differences in genome replication program and origin activation
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2020-06-30
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To ensure error-free duplication of all (epi)genetic information once per cell cycle, DNA replication follows a cell type and developmental stage specific spatio-temporal program. Here, we analyze the spatio-temporal DNA replication progression in (un)differentiated mouse embryonic stem (mES) cells. Whereas telomeres replicate throughout S-phase, we observe mid-S phase replication of (peri)centromeric heterochromatin in mES cells, which switches to late S-phase replication upon differentiation correlating with increase in condensation and decrease in acetylation of chromatin. We also find synchronous duplication of the Y chromosome, marking the end of S-phase, irrespectively of the pluripotency state. Using a combination of single-molecule and super-resolution microscopy, we measure molecular properties of the mES cell replicon, the number of replication foci active in parallel and their spatial clustering in mES cells versus somatic cells. We conclude that each replication nanofocus in mES cells corresponds to an individual replicon, with approximately up to one quarter representing unidirectional forks. Furthermore, with molecular combing and genome-wide origin mapping analyses we find that mES cells activate twice as many origins spaced at half the distance than somatic cells. Altogether, our results highlight fundamental developmental differences on progression of genome replication and origin activation in pluripotent cells.
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Except where otherwise noted, this license is described as CC-BY-NC 4.0 - Attribution-NonCommercial 4.0 International
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