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Transcriptionally Driven DNA Replication Programme of the Human Parasite Leishmania major

ABSTRACT: Faithful inheritance of the large eukaryotic genomes requires the orchestrated activation of multiple DNA replication origins. Although origin activation is mechanistically conserved among eukaryotes, how replication origins are specified and selected for activation in each S-phase seem to differ across the model systems studied. Here we provide a complete analysis of the nucleosomal landscape and replication programme of the human parasite Leishmania major, building on a better evolutionary understanding of replication organization in Eukarya. We found that active transcription is a driving force for the nucleosomal organization of L. major genome, and that both the spatial and the temporal programme of DNA replication can be explained as associated to RNA polymerase kinetics, without the need to invoke specific regulatory mechanisms. This simple scenario likely provides these organisms with the flexibility and robustness to deal with the continuous environmental changes that impose alterations in their genetic programmes during their parasitic life cycle stages. Our findings also suggest that coupling replication initiation to transcription elongation could be an ancient solution used by eukaryotic cells for origin maintenance

ORGANISM(S): Leishmania major strain Friedlin

PROVIDER: GSE81991 | GEO | 2016/06/10

SECONDARY ACCESSION(S): PRJNA323581

REPOSITORIES: GEO

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Transcriptionally Driven DNA Replication Programme of the Human Parasite Leishmania major

Project description:Faithful inheritance of the large eukaryotic genomes requires the orchestrated activation of multiple DNA replication origins. Although origin activation is mechanistically conserved among eukaryotes, how replication origins are specified and selected for activation in each S-phase seem to differ across the model systems studied. Here we provide a complete analysis of the nucleosomal landscape and replication programme of the human parasite Leishmania major, building on a better evolutionary understanding of replication organization in Eukarya. We found that active transcription is a driving force for the nucleosomal organization of L. major genome, and that both the spatial and the temporal programme of DNA replication can be explained as associated to RNA polymerase kinetics, without the need to invoke specific regulatory mechanisms. This simple scenario likely provides these organisms with the flexibility and robustness to deal with the continuous environmental changes that impose alterations in their genetic programmes during their parasitic life cycle stages. Our findings also suggest that coupling replication initiation to transcription elongation could be an ancient solution used by eukaryotic cells for origin maintenance Replication intitiation sites were defined using two replicates of short nascent strands of increasing sizes (F4 and F5) purified through three rounds of Lambda-exonuclease digestion, and a genomic DNA control (Ctrl). Nucleosome landscape was determined using two replicates of mononucleosomal-DNA derived from MNase-digested chromatin

2016-06-10 | E-GEOD-81991 | biostudies-arrayexpress

High-resolution genome replication profiles, modeling and single-cell imaging define the stochastic nature of replication initiation and termination

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2013-11-07 | E-GEOD-48561 | biostudies-arrayexpress

Forkhead transcription factors establish origin timing and long-range clustering in S. cerevisiae [Array Data]

Project description:The replication of eukaryotic chromosomes is organized temporally and spatially within the nucleus through epigenetic regulation of replication origin function. The characteristic initiation timing of specific origins is thought to reflect their chromatin environment or sub-nuclear positioning, however the mechanism remains obscure. Here we show that the yeast Forkhead transcription factors, Fkh1 and Fkh2, are global determinants of replication origin timing. Forkhead regulation of origin timing is independent of local levels or changes of transcription. Instead, we show that Fkh1 and Fkh2 are required for the clustering of early origins and their association with the key initiation factor Cdc45 in G1-phase, suggesting that Fkh1 and Fkh2 selectively recruit origins to emergent replication factories. Fkh1 and Fkh2 bind Fkh-activated origins, and interact physically with ORC, providing a plausible mechanism to cluster origins. These findings add a new dimension to our understanding of the epigenetic basis for differential origin regulation and its connection to chromosomal domain organization.

2012-01-20 | GSE33702 | GEO

Forkhead transcription factors establish origin timing and long-range clustering in S. cerevisiae [Sequence Data]

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Genome-wide EMSA (gEMSA) of ORC and yeast genomic DNA

Project description:Eukaryotic DNA replication origins are selected in G1-phase when the origin recognition complex (ORC) binds chromosomal DNA, triggering a series of molecular events that culminate in the initiation of DNA replication (a.k.a. origin firing) during S-phase. Each chromosome requires multiple origins for its duplication, and each origin fires at a characteristic time during S-phase, creating a cell-type specific genome replication pattern with relevance to differentiation, genome stability and evolution. It is unclear whether ORC-origin interactions are relevant to the regulation of origin activation time. Here we applied a novel genome-wide strategy to classify origins in the model eukaryote Saccharomyces cerevisiae based on the types of molecular interactions used for ORC-origin binding. Specifically, origins were classified as DNA-dependent when the strength of ORC-origin binding in vivo could be explained by the affinity of ORC for origin DNA in vitro, and, conversely, as ‘chromatin-dependent’ when the ORC-DNA interaction in vitro was insufficient to explain the strength of ORC-origin binding in vivo. The two classes of origins were distinct in terms of local nucleosome architecture and dependence on origin-flanking sequences in plasmid replication assays, consistent with local features of chromatin promoting ORC binding at ‘chromatin-dependent’ origins. Importantly, origins that fired in late S-phase, but not those that fired in early S-phase, showed a significant dependence on the ORC-origin DNA interaction for ORC binding in vivo. Therefore we demonstrate for the first time a connection between ORC-origin binding mechanisms and the regulation of origin activation time at a genome-wide level. Analysis of ORC genomic DNA binding across three ORC concentrations.

2013-09-30 | E-GEOD-48440 | biostudies-arrayexpress

Single molecule MATAC-seq reveals key determinants of DNA replication origin efficiency

Project description:Stochastic origin activation gives rise to significant cell-to-cell variability in the pattern of genome replication. The molecular basis for heterogeneity in efficiency and timing of individual origins is a long-standing question. Here, we developed Methylation Accessibility of TArgeted Chromatin domain Sequencing (MATAC-Seq) to determine single-molecule chromatin accessibility of specific genomic loci after targeted purification in their native chromatin context. Applying MATAC-Seq to selected early-efficient (EE) and late-inefficient (LI) budding yeast replication origins revealed large heterogeneity of chromatin states. Disruption of INO80 or ISW2 chromatin remodeling complexes leads to changes at individual nucleosomal positions that correlate with changes in their replication efficiency. We found a chromatin state with an optimal 100-115bp nucleosome-free region in combination with surrounding well-positioned nucleosomes and open +2 linker region is a strong predictor for efficient origin activation. Thus, MATAC-Seq identifies the large spectrum of alternative chromatin states that co-exist on a given locus previously masked in population-based experiments and provides a mechanistic basis for origin activation heterogeneity during DNA replication of eukaryotic cells. Consequently, our single-molecule assay for chromatin accessibility will be ideal to define single-molecule heterogeneity across many fundamental biological processes such as transcription, replication, or DNA repair in vitro and ex vivo.

2023-12-27 | GSE220757 | GEO

Forkhead transcription factors establish origin timing and long-range clustering in S. cerevisiae [Sequence Data]

2012-01-20 | E-GEOD-33677 | biostudies-arrayexpress

High-resolution genome replication profiles, modeling and single-cell imaging define the stochastic nature of replication initiation and termination

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High-Resolution Profiling of Drosophila Replication Start Sites Reveals a DNA Shape and Chromatin Signature of Metazoan Origins

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H4S47 O-GlcNAcylation regulates the activation of mammalian replication origins

Project description:The transmission and maintenance of genetic information in eukaryotic cells rely on the faithful duplication of the entire genome. In each round of division, excessive replication origiNS are licensed, while only a fraction is activated to give rise to bi-directional replication forks travelling in the context of chromatin. However, it remaiNS elusive how eukaryotic replication origiNS are selectively activated. Here we demoNStrate that O-GlcNAc traNSferase (OGT) enhances replication initiation by catalysing H4S47 O-GlcNAcylation. Mutation of H4S47 impairs DBF4-dependent protein kinase (DDK) recruitment on chromatin, causing compromised phosphorylation of replicative helicase mini-chromosome maintenance (MCM) complex. Meanwhile, our short nascent-strand sequencing (SNS-seq) confirms the important role of H4S47 O-GlcNAcylation in origin activation. Together, H4S47 O-GlcNAcylation directs origin activation through facilitating MCM phosphorylation, and this may shed light on the spatial and temporal control of DNA replication by the dynamically changing chromatin environment.

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