Replication timing of control and suv4-20h (KO and inducible mutant) cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Jean-Charles Cadoret
PROVIDER: E-GEOD-69084 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Although histone modifications have been implicated in many DNA-dependent processes, their precise role in DNA replication remains poorly understood. Here, we show that the regulation of histone H4-K20 methylation states, in particular for the monomethylation, is a critical determinant of licensing and time activation of replication origins in mammalian cells. Two experimental condition : shRNA LUC cells (control) versus siRNA Prset-7 cells
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Project description:The human A-family DNA polymerase M-NM-8 (Pol q) is a large, multidomain enzyme whose physiological function is still unclear despite its in vitro translesion synthesis capacity in front of DNA damage and its involvement in some features of DNA repair after external stress. Here we present evidence that Pol q holds a novel role in the absence of external stress as a critical determinant of the replication timing program in human cells. Pol q binds to chromatin at early G1 and is required for proper formation of pre-replicative complexe and replication origin activation. Pol q-depleted cells show modified spatial organization of chromatin-loop structures at replication factories. Genome-wide analysis of replication timing shows delayed replication of a part of early replicating domains and advanced replication of a part of late replicating domains following Pol q depletion. Our results identify Pol q as one of the first critical human factors discovered in the replication timing programme. Two-condition experiment, control vs. over expressed polQ cells. Biological replicates: 2 control replicates, 2 transfected replicates.
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Project description:The human A-family DNA polymerase M-NM-8 (Pol q) is a large, multidomain enzyme whose physiological function is still unclear despite its in vitro translesion synthesis capacity in front of DNA damage and its involvement in some features of DNA repair after external stress. Here we present evidence that Pol q holds a novel role in the absence of external stress as a critical determinant of the replication timing program in human cells. Pol q binds to chromatin at early G1 and is required for proper formation of pre-replicative complexe and replication origin activation. Pol q-depleted cells show modified spatial organization of chromatin-loop structures at replication factories. Genome-wide analysis of replication timing shows delayed replication of a part of early replicating domains and advanced replication of a part of late replicating domains following Pol q depletion. Our results identify Pol q as one of the first critical human factors discovered in the replication timing programme. Two-condition experiment, siRNA control vs. siRNA polQ cells. Biological replicates: 2 control replicates, 2 transfected replicates.
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Project description:Cell fate change involves significant genome reorganization, including change in replication timing, but how these changes are related to genetic variation has not been examined. To study how change in replication timing that occurs during reprogramming impacts the copy number variation (CNV) landscape, we generated genome-wide replication timing profiles of induced pluripotent stem cells (iPSCs) and their parental fibroblasts. A significant portion of the genome changes replication timing as a result of reprogramming, indicative of overall genome reorganization. We found that early and late replicating domains in iPSCs are differentially affected by copy number gains and losses, and that in particular CNV gains accumulate in regions of the genome that change to earlier replication during the reprogramming process. This differential relationship was present irrespective of reprogramming method. Overall, our findings reveal a functional association between reorganization of replication timing and the CNV landscape that emerges during reprogramming. 3 cell lines, all in duplicates
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Project description:We have investigated the role of the histone methyltransferase G9a in the establishment of silent nuclear compartments. Following conditional knockout of the G9a methyltransferase in mouse ESCs, 167 genes were significantly up-regulated, and no genes were strongly down-regulated. A partially overlapping set of 119 genes were up-regulated after differentiation of G9a-depleted cells to neural precursors. Promoters of these G9a-repressed genes were AT rich and H3K9me2 enriched but H3K4me3 depleted and were not highly DNA methylated. Representative genes were found to be close to the nuclear periphery, which was significantly enriched for G9a-dependent H3K9me2. Strikingly, although 73% of total genes were early replicating, more than 71% of G9a-repressed genes were late replicating, and a strong correlation was found between H3K9me2 and late replication. However, G9a loss did not significantly affect subnuclear position or replication timing of any non-pericentric regions of the genome, nor did it affect programmed changes in replication timing that accompany differentiation. We conclude that G9a is a gatekeeper for a specific set of genes localized within the late replicating nuclear periphery. 4 cell states each in duplicate (i.e. a total of 8 individual replicates)
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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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