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

journal contribution
posted on 2023-05-17, 12:36 authored by Hiratani, I, Ryba, T, Itoh, M, Rathjen, J, Kulik, M, Papp, B, Fussner, E, Bazett-Jones, D, Plath, K, Dalton, S, Rathjen, PD, Gilbert, DM
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 postimplantation 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 earlyto-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. © 2010 by Cold Spring Harbor Laboratory Press.


Publication title

Genome Research








Menzies Institute for Medical Research


Cold Spring Harbor Lab Press

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Publications Dept, 500 Sunnyside Blvd, Woodbury, USA, Ny, 11797-2924

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Expanding knowledge in the biological sciences

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