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Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis.

Genome Res, 2010/2;20(2):155-69.

Hiratani I[1], Ryba T, Itoh M, Rathjen J, Kulik M, Papp B, Fussner E, Bazett-Jones DP, Plath K, Dalton S, Rathjen PD, Gilbert DM

Affiliations

PMID: 19952138DOI: 10.1101/gr.099796.109

Impact factor: 9.438

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.
MeSH terms
Animals; Cell Differentiation; Cell Line; Chromatin; CpG Islands; DNA Replication Timing; Down-Regulation; Embryonic Development; Embryonic Stem Cells; Epigenesis, Genetic; Female; Gene Expression Regulation, Developmental; Genome-Wide Association Study; Germ Layers; Homeodomain Proteins; Mice; Nanog Homeobox Protein; Octamer Transcription Factor-3; Pluripotent Stem Cells; Promoter Regions, Genetic; SOXB1 Transcription Factors; Transcription, Genetic
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