title: Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis.
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.
authors: Department of Biological Science, Florida State University, Tallahassee, Florida 32306, USA.
authors: Ichiro
authors: I
authors: Hiratani
authors: Tyrone
authors: T
authors: Ryba
authors: Mari
authors: M
authors: Itoh
authors: Joy
authors: J
authors: Rathjen
authors: Michael
authors: M
authors: Kulik
authors: Bernadett
authors: B
authors: Papp
authors: Eden
authors: E
authors: Fussner
authors: David P
authors: DP
authors: Bazett-Jones
authors: Kathrin
authors: K
authors: Plath
authors: Stephen
authors: S
authors: Dalton
authors: Peter D
authors: PD
authors: Rathjen
authors: David M
authors: DM
authors: Gilbert
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002843:Chromatin / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D042522:DNA Replication Timing / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study; D005855:Germ Layers / Q000254:growth & development; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse