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The impact of chromatin modifiers on the timing of locus replication in mouse embryonic stem cells

Helle F Jørgensen1*, Véronique Azuara12, Shannon Amoils1, Mikhail Spivakov1, Anna Terry1, Tatyana Nesterova3, Bradley S Cobb1, Bernard Ramsahoye4, Matthias Merkenschlager1 and Amanda G Fisher1*

Author Affiliations

1 Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, London W12 0NN, UK

2 Current address: Institute of Reproductive and Developmental Biology, Imperial College School of Medicine, London W12 0NN, UK

3 Developmental Epigenetics, MRC Clinical Sciences Centre, Imperial College School of Medicine, London W12 0NN, UK

4 Developmental Epigenetics, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XR, UK

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Genome Biology 2007, 8:R169  doi:10.1186/gb-2007-8-8-r169

Published: 17 August 2007

Abstract

Background

The time of locus replication during S-phase is tightly regulated and correlates with chromatin state. Embryonic stem (ES) cells have an unusual chromatin profile where many developmental regulator genes that are not yet expressed are marked by both active and repressive histone modifications. This poised or bivalent state is also characterized by locus replication in early S-phase in ES cells, while replication timing is delayed in cells with restricted developmental options.

Results

Here we used a panel of mutant mouse ES cell lines lacking important chromatin modifiers to dissect the relationship between chromatin structure and replication timing. We show that temporal control of satellite DNA replication is sensitive to loss of a variety of chromatin modifiers, including Mll, Eed, Dnmt1, Suv39h1/h2 and Dicer. The replication times of many single copy loci, including a 5 Mb contiguous region surrounding the Rex1 gene, were retained in chromatin modifier mutant ES cells, although a subset of loci were affected.

Conclusion

This analysis demonstrates the importance of chromatin modifiers for maintaining correct replication of satellite sequences in pluripotent ES cells and highlights the sensitivity of some single copy loci to the influence of chromatin modifiers. Abundant histone acetylation is shown to correlate well with early replication. Surprisingly, loss of DNA methylation or histone methylation was tolerated by many loci, suggesting that these modifications may be less influential for the timing of euchromatin replication.