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Single-cell replication profiling reveals stochastic regulation of the mammalian replication-timing program

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE102077 | GEO | 2017/12/19

SECONDARY ACCESSION(S): PRJNA396545

REPOSITORIES: GEO

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Single-cell replication profiling reveals stochastic regulation of the mammalian replication-timing program [population]

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Single-cell replication profiling reveals stochastic regulation of the mammalian replication-timing program

Project description:Single-cell replication profiling reveals stochastic regulation of the mammalian replication-timing program

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Single-cell replication profiling to measure stochastic variation in mammalian replication timing.

Project description:Mammalian DNA replication is regulated via multi-replicon segments that replicate in a defined temporal order during S-phase. Further, early/late replication of RDs corresponds to active/inactive chromatin interaction compartments. Although replication origins are selected stochastically, variation in replication timing is poorly understood. Here we devise a strategy to measure variation in replication timing using DNA copy number in single mouse embryonic stem cells. We find that borders between replicated and unreplicated DNA are highly conserved between cells, demarcating active and inactive compartments of the nucleus. Fifty percent of replication events deviated from their average replication time by ± 15% of S phase. This degree of variation is similar between cells, between homologs within cells and between all domains genomewide, regardless of their replication timing. These results demonstrate that stochastic variation in replication timing is independent of elements that dictate timing or extrinsic environmental variation.

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Modeling genome-wide replication kinetics reveals a mechanism for regulation of replication timing.

Project description:Microarrays are powerful tools to probe genome-wide replication kinetics. The rich data sets that result contain more information than has been extracted by current methods of analysis. In this paper, we present an analytical model that incorporates probabilistic initiation of origins and passive replication. Using the model, we performed least-squares fits to a set of recently published time course microarray data on Saccharomyces cerevisiae. We extracted the distribution of firing times for each origin and found that the later an origin fires on average, the greater the variation in firing times. To explain this trend, we propose a model where earlier-firing origins have more initiator complexes loaded and a more accessible chromatin environment. The model demonstrates how initiation can be stochastic and yet occur at defined times during S phase, without an explicit timing program. Furthermore, we hypothesize that the initiators in this model correspond to loaded minichromosome maintenance complexes. This model is the first to suggest a detailed, testable, biochemically plausible mechanism for the regulation of replication timing in eukaryotes.

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Conservation of replication timing reveals global and local regulation of replication origin activity.

Project description:DNA replication initiates from defined locations called replication origins; some origins are highly active, whereas others are dormant and rarely used. Origins also differ in their activation time, resulting in particular genomic regions replicating at characteristic times and in a defined temporal order. Here we report the comparison of genome replication in four budding yeast species: Saccharomyces cerevisiae, S. paradoxus, S. arboricolus, and S. bayanus. First, we find that the locations of active origins are predominantly conserved between species, whereas dormant origins are poorly conserved. Second, we generated genome-wide replication profiles for each of these species and discovered that the temporal order of genome replication is highly conserved. Therefore, active origins are not only conserved in location, but also in activation time. Only a minority of these conserved origins show differences in activation time between these species. To gain insight as to the mechanisms by which origin activation time is regulated we generated replication profiles for a S. cerevisiae/S. bayanus hybrid strain and find that there are both local and global regulators of origin function.

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Embryonic genome instability upon DNA replication timing program emergence

Project description:This SuperSeries is composed of the SubSeries listed below.

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Profiling DNA Replication Timing in Zebrafish Embryos Reveals Dynamic Regulation During Development

Project description:The temporal order of DNA replication is modified during differentiation, but when a replication timing program is established and what alterations occur in vivo during embryogenesis are not known. Here we used zebrafish embryos to generate genome-wide, high-resolution replication timing maps throughout development. Unexpectedly, a non-random and defined replication timing program was evident in the rapid cell cycles before the midblastula transition. The majority of the genome undergoes dynamic shifts in replication timing throughout development as the timing program is decompressed, with many abrupt timing changes occurring during lineage specification. Strikingly, the long arm of chromosome 4 undergoes a developmentally regulated switch to late replication, reminiscent of mammalian X chromosome inactivation. This analysis also revealed a strong relationship between early replication and epigenetic marks at enhancers. Collectively, these data reveal the major changes in replication timing that occur during zebrafish embryogenesis, and demonstrate its dynamic regulation during vertebrate development.

2017-04-13 | GSE85713 | GEO

Conservation of replication timing reveals global and local regulation of replication origin activity.

Project description:DNA replication initiates from defined locations called replication origins; some origins are highly active whereas others are dormant and rarely used. Origins also differ in their activation time resulting in particular genomic regions replicating at characteristic times and in a defined temporal order. Here we report the comparison of genome replication in four budding yeast species: Saccharomyces cerevisiae, S. paradoxus, S. arboricolus and S. bayanus. First, we find that the locations of active origins are predominantly conserved between species, whereas dormant origins are poorly conserved. Second, we generated genome-wide replication profiles for each of these species and discovered that the temporal order of genome replication is highly conserved. Therefore, active origins are not only conserved in location, but also activation time. Only a minority of these conserved origins show differences in activation time between these species. To gain insight as to the mechanisms by which origin activation time is regulated we generated replication profiles for a S. cerevisiae / S. bayanus hybrid strain and find that there are both local and global regulators of origin function. Measurement of genome replication time from 4 budding yeast species (Saccharomyces cerevisiae, S. paradoxus, S. arboricolus and S. bayanus) and a hybrid (between Saccharomyces cerevisiae and S. bayanus). For each strain two samples were analysed: a replicating sample (from S phase) and a non-replicating sample (from G2 phase) The reference genome sequences for each yeast species are available as Series supplementary file [sac*.fa]

2012-06-19 | E-GEOD-36045 | biostudies-arrayexpress

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