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Genome-Wide Dynamics of Replication Timing Revealed by In Vitro Models of Mouse Embryogenesis (Expression)

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 lineage-independent 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 (Oct4/Nanog/Sox2) and coinciding with the emergence of compact chromatin near the nuclear periphery. These changes were conserved in all subsequent lineages 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. Taken together, we demonstrate that replication-timing changes are extensive during development. Moreover, a distinct set of lineage-independent, early-to-late changes completed in and stably maintained after the post-implantation epiblast stage is difficult to reprogram and therefore coincides with an epigenetic commitment to differentiation prior to germ layer specification.

ORGANISM(S): Mus musculus

PROVIDER: GSE17980 | GEO | 2009/11/25

SECONDARY ACCESSION(S): PRJNA123569

REPOSITORIES: GEO

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Project description:Extensive changes in replication timing occur during early mouse development, but their biological significance remains uncertain. To identify evolutionarily conserved features of replication timing and their relationships to epigenetic properties in humans, we profiled replication timing genome-wide in four human embryonic stem cell (hESC) lines, hESC-derived neural precursor cells (NPCs), lymphoblastoid cells, and two independently derived human induced pluripotent stem cell lines (hiPSCs). Results confirm the conservation of coordinately replicated megabase-sized units of chromosomes (replication domains) with stable cell type specific molecular boundaries that consolidate into larger replication domains during differentiation. Replication timing changes encompassed units of 400-800 kb and were coordinated with changes in transcription similar to mouse. Moreover, significant cell-type specific conservation of replication timing profiles was observed across regions of conserved synteny, despite significant species variation in the alignment of replication timing to isochore GC/LINE-1 content. Replication profiling also revealed a closer genome-wide epigenetic alignment of hESCs to mouse epiblast-derived stem cells (mEpiSCs) than to mouse ESCs. Finally, we identify a signature of chromatin modifications marking the boundaries of early replicating domains and a remarkably strong link between spatial proximity of chromatin as measured by Hi-C analysis and replication timing. Together, our results reveal evolutionarily conserved elements of the replication program in mammalian early development, demonstrate the power of replication profiling to identify important epigenetic distinctions between closely related stem cell populations (e.g. ESCs vs. EpiSCs), and strengthen the hypothesis that replication domains are structural and functional units of 3D chromosomal architecture. 8 cell types, with a total of 13 individual replicates (i.e. 5 in duplicates, 3 in single replicates)

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Genome-Wide Dynamics of Replication Timing Revealed by In Vitro Models of Mouse Embryogenesis (Expression)

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