Genome-wide mapping of DNA damage hotspots in response to various replication stressors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE113020 | GEO | 2019/06/24
REPOSITORIES: GEO
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Project description:Genome-wide mapping of DNA damage hotspots in response to various replication stressors
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Project description:We recently developed high-throughput sequencing approaches, eXcision Repair sequencing (XR-seq) and Damage-seq, to generate genome-wide mapping of DNA damage formation and excision repair, respectively, with single-nucleotide resolution. Here, we adopted time-course XR-seq data to profile UV-induced excision repair dynamics, paired with Damage-seq data to quantify the overall induced DNA damage. We identified genome-wide repair hotspots that are subject to exemplified amount of repair very soon after UV irradiation. We show that such repair hotspots do not result from hypersensitivity to DNA damage and are thus not damage hotspots. We find that the earliest repair occur preferentially in promoters and enhancers from open-chromatin regions. The repair hotspots are also significantly enriched for frequently interacting regions and super-enhancers, both of which are hotspots for local chromatin interactions. We further extend the interrogation of chromatin organization to DNA replication timing and conclude that early-repair hotspots are enriched for early-replication domains. Collectively, we report genome-wide early-repair hotspots of UV-induced damage, in association with chromatin states and epigenetic compartmentalization of the human genome.
2020-04-09 | GSE148303 | GEO
Project description:In our project we are using the Top2 inhibitor, ICRF-193, in order to induce damage in NIH3T3 MEFs. We report the high-throughput identification of genomic hotspots for damage induction by ICRF-193, using γH2AX as a marker. We find that ICRF-193 primarily induces damage in repetitive sequences, which are known to reside in regions of heterochromatin, with a very small portion of damaged sites residing in regions of active genes in euchromatin. Overall, this study provides evidence that catalytic inhibition of Top2 enzymes by ICRF-193, leads to induction of damage in the nuclear sub-compartments of heterochromatin.
2024-04-17 | GSE256090 | GEO
Project description:Genetic recombination generates novel trait combinations, and understanding how recombination is distributed across the genome is key to modern genetics. The PRDM9 protein defines recombination hotspots; however, megabase-scale recombination patterning is independent of PRDM9. The single round of DNA replication, which precedes recombination in meiosis, may establish these patterns; therefore, we devised an approach to study meiotic replication that includes robust and sensitive mapping of replication origins. We find that meiotic DNA replication is distinct; reduced origin firing slows replication in meiosis, and a distinctive replication pattern in human males underlies the subtelomeric increase in recombination. We detected a robust correlation between replication and both contemporary and historical recombination and found that replication origin density coupled with chromosome size determines the recombination potential of individual chromosomes. Our findings and methods have implications for understanding the mechanisms underlying DNA replication, genetic recombination, and the landscape of mammalian germline variation.
2021-07-02 | GSE148327 | GEO
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.
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Project description:Prophage-encoded hotspots of anti-phage systems
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Project description:In human leukemia, lineage-specific genes represent predominant targets of deletion, with lymphoid-specific genes frequently affected in lymphoid leukemia and myeloid-specific genes in myeloid leukemia. To investigate the basis of lineage-specific alterations, we analyzed global DNA damage in primary B-cell precursors expressing leukemia-inducing oncogenes by ChIP-Seq. We identified >1000 sensitive regions, of which B-lineage-specific genes constitute the most prominent targets. Identified hotspots at B-lineage genes relate to DNA-DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic deletion in successfully transformed cells. We further show that most identified regions overlap with gene bodies of highly expressed genes, and that induction of a myeloid lineage phenotype in transformed B-cell precursors promotes de novo DNA damage at myeloid loci. Hence, we demonstrate that lineage-specific transcription predisposes lineage-specific genes in transformed B-cell precursors to DNA damage, which is likely to promote the frequent alteration of lineage-specific genes in human leukemia.
2017-02-13 | GSE80682 | GEO
Project description:Here we have used a combination of advanced proteomics and genomics approaches to investigate the extent and mechanisms of transcription factor cross-talk at genomic hotspots. We identify ~12,000 transcription factor hotspots in the early phase of adipogenesis, and we find evidence of both simultaneous and sequential binding of transcription factors at these regions. We demonstrate for the first time that hotspots are highly enriched in large super-enhancer regions and that these drive the early adipogenic reprogramming of gene expression. Our results indicate that cooperativity between transcription factors at the level of hotspots as well as super-enhancers is very important for enhancer activity and transcriptional reprogramming. Thus, hotspots and super-enhancers constitute important regulatory hubs integrating external stimuli on chromatin. Genome-wide profiling of transcription factor and co-factor binding, epigenomic marks, and gene expression in 3T3-L1 pre-adipocytes.
2014-04-17 | E-GEOD-56872 | biostudies-arrayexpress
Project description:Identification of sites of replication initiation by copy number analysis, comparing samples before and after entry into S phase. Experiments were performed in the following strains and conditions for mitotic cells: cdc25-22 (temperature-sensitive mutation arrests cells at G2/M for synchrony, otherwise wild type), nitrogen-rich conditions; wild type, haploid and diploid, nitrogen-depletion conditions. Experiments were performed in the following strains and conditions for meiotic cells: pat1-114 diploid (temperature-sensitive mutation induces a synchronous meiosis, otherwise wild type), nitrogen-depletion and nitrogen-rich conditions; pat1-114 diploid with altered Cdc45 levels, nitrogen-depletion conditions. Comparison of samples before and after S phase entry; dye-swap experiments were performed and averaged.
2014-02-20 | E-GEOD-53879 | biostudies-arrayexpress
Project description:Meiotic recombination, crucial for proper chromosome segregation and genome evolution, is initiated by programmed DNA double-strand breaks (DSBs) in budding and fission yeasts and likely all sexually reproducing species. In fission yeast, DSBs occur up to several hundred times more frequently at special sites, called hotspots, than in other regions of the genome. What distinguishes hotspots from cold regions is a major unsolved problem, although transcription factors determine some hotspots. We report here the discovery that three coiled-coil proteins -- Rec25, Rec27, and Mug20 -- bind essentially all hotspots with unprecedented, high specificity even without DSB formation. These small proteins are components of linear elements, are related to synaptonemal complex proteins, and are essential for nearly all DSBs at most hotspots. Our results indicate that these hotspot determinants activate or stabilize the DSB-forming protein Rec12 (Spo11 homolog) rather than promote its binding to hotspots. We propose here a new paradigm for hotspot determination and crossover control by linear element proteins.
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