Replication timing and epigenetic reprogramming of gene expression: a two-way relationship?

Abstract

An overall link between the potential for gene transcription and the timing of replication in S phase is now well established in metazoans. Here we discuss emerging evidence that highlights the possibility that replication timing is causally linked with epigenetic reprogramming. In particular, we bring together conclusions from a range of studies to propose a model in which reprogramming factors determine the timing of replication and the implementation of reprogramming events requires passage through S phase. These considerations have implications for our understanding of development, evolution and diseases such as cancer.

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Figure 1: The relationship between origin spacing, replicon size and replication timing.
Figure 2: Epigenetic regulation of replication origin licensing and firing.
Figure 3: The epigenetic allegiances of the replication fork.
Figure 4: Chromatin loops and coordination of replication origin firing.

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Acknowledgements

We apologize that we are unable to discuss all observations relevant to the topics covered in this article owing to space limitations. We gratefully acknowledge D. Gilbert, A.P. Feinberg, D. Barlow, M. Debatisse and T. Helleday for valuable discussions. This work was supported by the Swedish Science Research Council, the Swedish Cancer Research Foundation, the Swedish Pediatric Cancer Foundation, the Lundberg Foundation and HEROIC and ChILL (EU integrated projects).

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Glossary

Asynchronous replication timing

The situation in which the two parental alleles replicate at different times during S phase.

CpG island

Sequences of 200 bp or more that have a high GC content and a high frequency of CpG dinucleotides.

Epigenetic reprogramming

The erasure and remodelling of epigenetic marks during mammalian development.

Genomic imprinting

Monoallelic expression in a parent of origin-dependent manner.

Heterochromatic block

A region in a chromosome that is tightly coiled and generally inactive in terms of gene expression.

Pan-S replication

Sequences replicating throughout S phase in a cell population.

Pre-replication complex

A protein complex that forms at the replication origin before initiation of DNA replication.

Replication origin

A sequence at which replication is initiated.

Replicon

A region of DNA that replicates from a single origin of replication.

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Göndör, A., Ohlsson, R. Replication timing and epigenetic reprogramming of gene expression: a two-way relationship?. Nat Rev Genet 10, 269–276 (2009). https://doi.org/10.1038/nrg2555

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