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

• Published in: Genome research Vol. 20; no. 2; pp. 155 - 169
• Main Authors: Hiratani, Ichiro, Ryba, Tyrone, Itoh, Mari, Rathjen, Joy, Kulik, Michael, Papp, Bernadett, Fussner, Eden, Bazett-Jones, David P, Plath, Kathrin, Dalton, Stephen, Rathjen, Peter D, Gilbert, David M
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01-02-2010
• Subjects: Animals; Cell Differentiation - genetics; Cell Line; Chromatin - genetics; CpG Islands - genetics; DNA Replication Timing - genetics; Down-Regulation - genetics; Embryonic Development - genetics; Embryonic Stem Cells - cytology; Epigenesis, Genetic - genetics; Female; Gene Expression Regulation, Developmental; Genome-Wide Association Study; Germ Layers - growth & development; Homeodomain Proteins - genetics; Mice; Nanog Homeobox Protein; Octamer Transcription Factor-3 - genetics; Pluripotent Stem Cells - cytology; Promoter Regions, Genetic - genetics; SOXB1 Transcription Factors - genetics; Transcription, Genetic - genetics
• ISSN: 1088-9051; 1549-5469
• DOI: 10.1101/gr.099796.109

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.