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Transcription Initiation Activity Sets Replication Origin Efficiency in Mammalian Cells

ABSTRACT: Genomic mapping of DNA replication origins (ORIs) in mammals provides a powerful means for understanding the regulatory complexity of our genome. Here we combine a genome-wide approach to identify preferential sites of DNA replication initiation at 0.4% of the mouse genome with detailed molecular analysis at distinct classes of ORIs according to their location relative to the genes. Our study reveals that 85% of the replication initiation sites in mouse embryonic stem (ES) cells are associated with transcriptional units. Nearly half of the identified ORIs map at promoter regions and, interestingly, ORI density strongly correlates with promoter density, reflecting the coordinated organisation of replication and transcription in the mouse genome. Detailed analysis of ORI activity showed that CpG island promoter-ORIs are the most efficient ORIs in ES cells and both ORI specification and firing efficiency are maintained across cell types. Remarkably, the distribution of replication initiation sites at promoter-ORIs exactly parallels that of transcription start sites (TSS) suggesting a co-evolution of the regulatory regions driving replication and transcription. Moreover, we found that promoter-ORIs are significantly enriched in CAGE tags derived from early embryos relative to all promoters. This association implies that transcription initiation early in development sets the probability of ORI activation unveiling a new hallmark in ORI efficiency regulation in mammalian cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE15082 | GEO | 2009/03/05

SECONDARY ACCESSION(S): PRJNA114781

REPOSITORIES: GEO

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Transcription Initiation Activity Sets Replication Origin Efficiency in Mammalian Cells

Project description:Genomic mapping of DNA replication origins (ORIs) in mammals provides a powerful means for understanding the regulatory complexity of our genome. Here we combine a genome-wide approach to identify preferential sites of DNA replication initiation at 0.4% of the mouse genome with detailed molecular analysis at distinct classes of ORIs according to their location relative to the genes. Our study reveals that 85% of the replication initiation sites in mouse embryonic stem (ES) cells are associated with transcriptional units. Nearly half of the identified ORIs map at promoter regions and, interestingly, ORI density strongly correlates with promoter density, reflecting the coordinated organisation of replication and transcription in the mouse genome. Detailed analysis of ORI activity showed that CpG island promoter-ORIs are the most efficient ORIs in ES cells and both ORI specification and firing efficiency are maintained across cell types. Remarkably, the distribution of replication initiation sites at promoter-ORIs exactly parallels that of transcription start sites (TSS) suggesting a co-evolution of the regulatory regions driving replication and transcription. Moreover, we found that promoter-ORIs are significantly enriched in CAGE tags derived from early embryos relative to all promoters. This association implies that transcription initiation early in development sets the probability of ORI activation unveiling a new hallmark in ORI efficiency regulation in mammalian cells. Two biological replicates of lambda-exonuclease treated short nascent strands (100-600 or 300-800 nt in length) were co-hybridised with genomic DNA from the same cells to tiled genomic array covering 10.1 Mb of the mouse genome (Agilent Technologies)

2010-05-22 | E-GEOD-15082 | biostudies-arrayexpress

Genome-scale analysis of metazoan replication origins reveals their organization in specific but flexible sites defined by conserved features.

Project description:In metazoans, thousands of DNA replication origins (Oris) are activated to replicate DNA at each cell cycle. Although their timing of activation is better understood, their genomic organization and their genetic nature remain elusive. Here, we identified Oris by nascent strand (NS) purification and characterized their common features by performing a genome-wide analysis in both Drosophila and mouse cell lines. We show that in both species most CpG islands (CGI) contain Oris, although methylation is nearly absent in Drosophila, suggesting that this epigenetic mark is not crucial for defining the initiation event. Moreover, nascent strands at the borders of CGIs show a striking bimodal distribution, suggestive of a dual initiation event. We also found that Oris contain a unique nucleotide skew around NS peaks, characterized by G/T and C/A over-representation at 5’ and 3’ of the Ori sites, respectively. GC-rich elements are detected, which are good predictors of Oris, in both mouse and Drosophila, suggesting that common sequence features are part of metazoan Oris. In the heterochromatic chromosome 4 of Drosophila, Oris are strongly correlated with HP1 binding sites. At the chromosome level, we show that Oris are organized in Ori-rich and -poor regions that co-localize with early and late replicating domains, respectively. Finally, the genome-wide analysis was coupled with a DNA combing analysis of the in-vivo spacing of replication origins. The results suggest that Oris are in large excess, and organized in groups of site-specific but flexible origins that define replicons, where a single origin is used in each group. This organization provides both site specificity and Ori firing flexibility in each replicon, allowing possible adaptation of DNA replication to environmental cues and cell fates.

2011-07-28 | GSE29183 | GEO

DNA replication origins in whole Arabidopsis seedlings

Project description:Full genome replication in eukaryotes depends on the function of thousands of DNA replication origins (ORIs). The genome-wide identification of ORI location, achieved for animal and plant cells in culture, has been important to define their DNA and chromatin features. A major challenge in the field is to approach the biology of ORIs in whole organisms to understand their developmental plasticity. Here, we have determined the ORI location, activity and chromatin landscape in two developmental stages of Arabidopsis thaliana. We found that ORIs associate with multiple chromatin signatures including the most frequent at TSS but also at proximal and distal gene regulatory regions or repressed Polycomb domains. In constitutive heterochromatin, a high fraction of ORIs colocalize with GC-rich retrotransposons. Quantitative analysis of ORI activity led us to conclude that strong ORIs possess high scores of local GC content and clusters of GGN trinucleotides that may form G quadruplexes and other G-rich structures. We also found that development primarily influences ORI firing strength rather than the location of ORIs in different genomic loci. Moreover, ORIs that preferentially fire at early vegetative stages colocalize with GC-rich heterochromatin whereas those at later stages associate with transcribed genes. Our results provide the first identification of ORI features in a whole organism, opening new ways of studying DNA replication in different cell types in the context of development under normal and mutant conditions.

2018-04-15 | GSE109668 | GEO

Genome-wide mapping of human DNA-replication origins: levels of transcription at Orc1 sites regulate origin selection and replication timing

Project description:We report the genome-wide mapping of Orc1 binding-sites in mammals and their validation as active DNA-replication origins (ORIs). Orc1 sites are universally associated with transcription start sites (TSSs) of coding or non-coding RNAs. Transcription levels at the Orc1 sites directly correlate with replication timing, suggesting the existence of two classes of ORIs: those associated with moderate/high transcription levels (M-bM-^IM-%1 RNA copy/cell), replicating in early S and mapping to the TSSs of coding RNAs, and those associated with low transcription levels (<1 RNA copy/cell), replicating throughout the entire S and mapping to TSSs of non-coding RNAs. These findings are compatible with a scenario whereby TSS expression-levels influence the efficiency of Orc1 recruitment at G1 and the probability of firing during S. Identification of Orc1 binding sites in human cells

2012-09-18 | E-GEOD-37583 | biostudies-arrayexpress

Genome-wide mapping of human DNA-replication origins: levels of transcription at Orc1 sites regulate origin selection and replication timing

Project description:We report the genome-wide mapping of Orc1 binding-sites in mammals and their validation as active DNA-replication origins (ORIs). Orc1 sites are universally associated with transcription start sites (TSSs) of coding or non-coding RNAs. Transcription levels at the Orc1 sites directly correlate with replication timing, suggesting the existence of two classes of ORIs: those associated with moderate/high transcription levels (≥1 RNA copy/cell), replicating in early S and mapping to the TSSs of coding RNAs, and those associated with low transcription levels (<1 RNA copy/cell), replicating throughout the entire S and mapping to TSSs of non-coding RNAs. These findings are compatible with a scenario whereby TSS expression-levels influence the efficiency of Orc1 recruitment at G1 and the probability of firing during S.

2012-09-18 | GSE37583 | GEO

Mus musculus

Project description:Transcription Initiation Activity Sets Replication Origin Efficiency in Mammalian Cells

| PRJNA114781 | ENA

Chromatin environment shapes replication origin organization and defines origin classes

Project description:To unveil the still-elusive nature of metazoan replication origins, we identified them genome-wide and at unprecedented high-resolution in mouse ES cells. This allowed initiation sites (IS) and initiation zones (IZ) to be differentiated. We then characterized their genetic signatures and organization and integrated these data with 43 chromatin marks and factors. Our results reveal that replication origins can be grouped into three main classes with distinct organization, chromatin environment and sequence motifs. Class 1 contains relatively isolated, low-efficiency origins that are poor in epigenetic marks and are enriched in an asymmetric AC repeat at the initiation site. Late origins are mainly found in this class. Class 2 origins are particularly rich in enhancer elements. Class 3 origins are the most efficient and are associated with open chromatin and polycomb protein-enriched regions. The presence of Origin G-rich Repeated elements (OGRE) potentially forming G-quadruplexes (G4) was confirmed at most origins. These coincide with nucleosome-depleted regions located upstream of the initiation sites, which are associated with a labile nucleosomes containing H3K64ac. These data demonstrate that specific chromatin landscapes and combinations of specific signatures regulate origin localization. They explain the frequently-observed links between DNA replication and transcription. They also emphasize the plasticity of metazoan replication origins, and suggest that in multicellular eukaryotes, the combination of distinct genetic features and chromatin configurations act in synergy to define and adapt the origin profile.

2015-10-14 | GSE68347 | GEO

Nucleosomal organization of replication origins and meiotic recombination hotspots in fission yeast

Project description:In Schizosaccharomyces pombe, DNA replication origins (ORIs) and meiotic recombination hotspots lack consensus sequences and show a bias towards mapping at large intergenic regions (IGRs). To explore whether this preference depended on underlying chromatin features, we have generated genome-wide nucleosome profiles during mitosis and meiosis. We have found that meiotic double-strand break sites (DSB) colocalize strictly with nucleosome-depleted regions (NDRs) and that large IGRs include clusters of NDRs that overlap with almost half of all DSBs. By contrast, ORIs do not colocalize with NDRs and they are regulated independently of DSBs. Physical relocation of NDRs at ectopic loci or modification of their genomic distribution during meiosis was paralleled by the generation of new DSB sites. Over 80% of all meiotic DSBs colocalize with NDRs that are also present during mitosis, indicating that the recombination pattern is largely dependent on constitutive properties of the genome and, to a lesser extent, on the transcriptional profile during meiosis. The organization of ORIs and of DSBs regions in S. pombe reveals similarities and differences relative to Saccharomyces cerevisiae.

2011-12-31 | GSE28879 | GEO

Temporal Regulation of Head-on Transcription at Replication Initiation Sites

Project description:Temporal Regulation of Head-on Transcription at Replication Initiation Sites

| PRJNA832854 | ENA

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