Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis
- Ichiro Hiratani1,
- Tyrone Ryba1,
- Mari Itoh1,
- Joy Rathjen2,
- Michael Kulik3,
- Bernadett Papp4,
- Eden Fussner5,
- David P. Bazett-Jones5,
- Kathrin Plath4,
- Stephen Dalton3,
- Peter D. Rathjen2 and
- David M. Gilbert1,6
- 1 Department of Biological Science, Florida State University, Tallahassee, Florida 32306, USA;
- 2 Department of Zoology, University of Melbourne, Parkville, Victoria 3010, Australia;
- 3 Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602, USA;
- 4 University of California Los Angeles, David Geffen School of Medicine, Department of Biological Chemistry, Jonsson Comprehensive Cancer Center, Molecular Biology Institute, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Los Angeles, California 90024, USA;
- 5 Program in Genetics and Genome Biology, The Hospital for Sick Children, Research Institute, Toronto, Ontario M5G 1L7, Canada
Abstract
Differentiation of mouse embryonic stem cells (mESCs) is accompanied by changes in replication timing. To explore the relationship between replication timing and cell fate transitions, we constructed genome-wide replication-timing profiles of 22 independent mouse cell lines representing 10 stages of early mouse development, and transcription profiles for seven of these stages. Replication profiles were cell-type specific, with 45% of the genome exhibiting significant changes at some point during development that were generally coordinated with changes in transcription. Comparison of early and late epiblast cell culture models revealed a set of early-to-late replication switches completed at a stage equivalent to the post-implantation epiblast, prior to germ layer specification and down-regulation of key pluripotency transcription factors [POU5F1 (also known as OCT4)/NANOG/SOX2] and coinciding with the emergence of compact chromatin near the nuclear periphery. These changes were maintained in all subsequent lineages (lineage-independent) and involved a group of irreversibly down-regulated genes, at least some of which were repositioned closer to the nuclear periphery. Importantly, many genomic regions of partially reprogrammed induced pluripotent stem cells (piPSCs) failed to re-establish ESC-specific replication-timing and transcription programs. These regions were enriched for lineage-independent early-to-late changes, which in female cells included the inactive X chromosome. Together, these results constitute a comprehensive “fate map” of replication-timing changes during early mouse development. Moreover, they support a model in which a distinct set of replication domains undergoes a form of “autosomal Lyonization” in the epiblast that is difficult to reprogram and coincides with an epigenetic commitment to differentiation prior to germ layer specification.
Footnotes
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↵6 Corresponding author.
E-mail gilbert{at}bio.fsu.edu; fax (850) 645-8447.
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[Supplemental material is available online at http://www.genome.org. The microarray data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession no. GSE18019.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.099796.109.
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- Received August 18, 2009.
- Accepted November 20, 2009.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press