The division of genomes into distinct replication time zones has long been established. However, an in-depth understanding of their organization and their relationship to transcription is incomplete. Taking advantage of a novel synchronization method ("baby machine") and of genomic DNA microarrays, we have, for the first time, mapped replication times of the entire mouse genome at a high temporal resolution. Our data revealed that although most of the genome has a distinct time of replication either early, middle, or late S phase, a significant portion of the genome is replicated asynchronously. Analysis of the replication map revealed the genomic scale organization of the replication time zones. We found that the genomic regions between early and late replication time zones often consist of extremely large replicons. Analysis of the relationship between replication and transcription revealed that early replication is frequently correlated with the transcription potential of a gene and not necessarily with its actual transcriptional activity. These findings, along with the strong conservation found between replication timing in human and mouse genomes, emphasize the importance of replication timing in transcription regulation.
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Acknowledgements. Stepwise tumorigenesis systems were kindly provided by William C Hahn (Dana-Farber Cancer Institute). Transcriptome analyses were performed using BRB-ArrayTools developed by Dr. Richard Simon and BRB-ArrayTools Development Team. We thank the European Commission (LSHC-CT-2005-518417 ‘Epitron’, HEALTH-F4-2007-200767 ‘Apo-Sys’H Gronemeyer and O Kallioniemi laboratories), the Ligue Contre le Cancer (H Gronemeyer, equipe labellisée), the Association pour la recherche sur le cancer (ARC), the Agence Nationale de la Recherche (ANR) and the Institut National du Cancer (INCa) for financial support. We thank Irene Yujnovsky and Maximiliano Portal for helpful discussions and critical reading of the manuscript and Dorothée Jean for technical assistance. Yelyzaveta Shlyakhtina is a recipient of a Doctoral Fellowship from the IGBMC International PhD Program, Danilo G Ceschin was a recipient of a Postdoctoral fellowship from Foundation pour la Recherche Medicale and Valeria Pavet was a recipient of a Senior Postdoctoral fellowship from the Ligue Contre le Cancer.