Lipid overload-induced DNA double stands breaks foci in HCC genome
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE272542 | GEO | 2025/12/04
REPOSITORIES: GEO
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Project description:Efficient repair of DNA double-strand breaks (DSBs) requires a coordinated DNA Damage Response (DDR), which includes phosphorylation of histone H2Ax, forming γH2Ax. This histone modification spreads beyond the DSB into neighboring chromatin, generating a DDR platform that protects against end disassociation and degradation, minimizing chromosomal rearrangements. However, mechanisms that determine the breadth and intensity of γH2Ax domains remain unclear. Here, we show that chromosomal contacts of a DSB site are the primary determinants for γH2Ax landscapes. DSBs that disrupt a topological border permit extension of γH2Ax domains into both adjacent compartments. In contrast, DSBs near a border produce highly asymmetric DDR platforms, with γH2Ax nearly absent from one broken end. Collectively, our findings lend insights into a basic DNA repair mechanism and how the precise location of a DSB may influence genome integrity.
2020-05-13 | GSE150384 | GEO
Project description:DDX49 is a RNA-binding protein, to explore DDX40 related RNAs in MASLD and MASH, we used RIP-seq to analysis to identify the mRNAs bound by DDX49 in HHL5 cells transfected with Flag tagged DDX49 following OA/PA treatment for 24 hours
2025-06-17 | GSE299232 | GEO
Project description:Neuronal activity causes the rapid expression of immediate early genes that are crucial for experience driven changes to synapses, learning, and memory. Here, using both molecular and genome-wide next generation sequencing methods, we report that neuronal activity stimulation triggers the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including Fos, Npas4, and Egr1. Generation of targeted DNA DSBs within Fos and Npas4 promoters is sufficient to induce their expression even in the absence of an external stimulus. Activity-dependent DSB formation is likely mediated by the type II topoisomerase, Topoisomerase IIb (Topo IIb), and knockdown of Topo IIb attenuates both DSB formation and early response gene expression following neuronal stimulation. Our results suggest that DSB formation is a physiological event that rapidly resolves topological constraints to early-response gene expression in neurons. Generation of sequencing data from ChIP-seq with antibodies against γH2AX and Topo IIβ after neuronal activity stimulation, and RNA-seq after etoposide treatment
2015-06-04 | E-GEOD-61887 | biostudies-arrayexpress
Project description:High concentration of NaCl increases DNA breaks both in cell culture and in vivo. The breaks remain elevated as long as NaCl concentration remains high and are rapidly repaired when the concentration is lowered. Repair of the breaks after NaCl is reduced is accompanied by formation of foci containing phosphorylated H2AX (γH2AX), which occurs around DNA double-strand breaks and contributes to their repair. By chromatin immunoprecipitation using anti-γH2AX antibody, followed by massive parallel sequencing (ChIP-Seq), we find that during repair of double–strand breaks induced by high NaCl, γH2AX is predominantly localized to regions of the genome devoid of genes (“gene deserts”), indicating that the high NaCl-induced double-strand breaks are located there. Localization to gene deserts helps explain why the DNA breaks are less harmful than are the random breaks induced by genotoxic agents such as UV radiation, ionizing radiation and oxidants. We propose that the universal presence of NaCl around animal cells has directly influenced the evolution of the structure of their genomes.
2011-11-21 | GSE32882 | GEO
Project description:In Saccharomyces cerevisiae, a single double-strand break (DSB) triggers extensive phosphorylation of histone H2A (known as gammaH2AX) over 50 kb on either side of the DSB. This modification is carried out by either of yeastM-^Rs checkpoint kinases, the ATM homolog, Tel1, or the ATR homolog, Mec1. In G1-arrested cells, where there is very little 5M-^R to 3M-^R processing of DSB ends, only Tel1 promotes this modification. We have recently described a second modification gammaH2B - the phosphorylation of the C terminal T129 locus of histone H2B which is also carried out by both Mec1 and Tel1 kinases. To understand in detail how gamma-H2AX and gamma-H2B spread along the chromosome from a DSB we have undertaken a high-density analysis of their occupancy where there is a DSB on three different chromosomes. gamma-H2AX and gamma-H2B modifications are similar, but there is a marked absence of gamma-H2B near telomeres. We find that there is reduced gamma-H2AX and gamma-H2B modification over strongly transcribed regions, even taking into account the reduced histone occupancy of these genes. When transcription of the galactose-regulated genes GAL1, GAL10, GAL7 are turned off by the addition of glucose, gamma-H2AX is restored within 5 min; when these genes are again induced, gamma-H2AX is rapidly lost. Regions more distal to the GAL genes have markedly reduced gamma-H2AX levels that rise rapidly when transcription is repressed, suggesting that transcription acts as a barrier to the propagation of gamma-H2AX away from the DSB. The restoration of gamma-H2AX in transcribed regions can be carried out by either Mec1 or Tel1, even 7 h after break induction, suggesting that Tel1 remains associated with damaged chromosomes for an extended time. In addition, we show that gamma-H2AX can be transferred in trans, to regions unlinked to the DSB that lie in close proximity the DSB. Specifically, if a DSB is generated 14 kb from CEN2, gamma-H2AX is transferred to regions around all the other centromeres, in keeping with observed close proximity of all centromere-adjacent chromosome arms. This transfer can be observed even in the absence of formaldehyde crosslinking of the samples.
2013-12-15 | E-MTAB-1409 | biostudies-arrayexpress
Project description:DNA Double-Strand Breaks (DSBs) are highly detrimental since they can lead to mutations and chromosomes rearrangements (amplification, deletion, translocation and chromosome loss). Here, we set to assess the tridimensional genome organization around DSBs and its role in DSB repair foci formation. We performed Hi-C experiments before and after DSB induction and upon ctrl or SCC1 depletion, 4C-seq experiments before and after DSB induction and upon cohesin (SCC1) depletion or ATM inhibition. We also performed ChIP-seq of pATM(S1981), CTCF, P-SMC3(S1083), MDC1 and a calibrated ChIP-seq of SCC1 with or without damage. ChIP-chip of SMC3 (S1083) and SMC1 (S966) were used to show the recruitment of these marks on DNA repair foci. ChIP-chip of gammaH2AX was realized upon SCC1 depletion and ChIP-seq of gammaH2AX was realized upon SCC1 or WAPL to show the role of the cohesin complex in gammaH2AX foci formation. ChIP-seq of gammaH2AX was realized upon ATM or ATR inhibition to show that ATM is the major kinase that phosphorylates H2AX at clean breaks in human cells.
2021-01-29 | E-MTAB-8851 | biostudies-arrayexpress
Project description:Chromatin acts as a key regulator of DNA related processes such as DNA damage repair. While ChIP-chip is a powerful technique to provide high-resolution maps of protein-genome interactions, its use to study DNA Double Strand Break (DSB) repair has been hindered by the limitations of the available damage induction methods. We have developed a human cell line that permits induction of multiple DSBs randomly distributed and unambiguously positioned within the genome. Using this system, we have generated the first genome-wide mapping of gammaH2AX around DSBs. We found that all DSBs trigger large gammaH2AX domains, which extend from the DSB in a bidirectional, discontinuous and not necessarily symmetrical manner. Strikingly we uncovered that, within domains, gammaH2AX distribution is highly influenced by gene transcription since parallel mapping of RNA Polymerase II and strand specific expression revealed that ?H2AX does not propagate on active genes. In addition, we demonstrate that transcription is accurately maintained within gammaH2AX domains, indicating that mechanisms may exist to protect genes transcription from gammaH2AX spreading and from the chromatin rearrangements induced by DSBs.
2010-04-20 | E-MEXP-1769 | biostudies-arrayexpress
Project description:DNA Double Strand Breaks (DSBs) are a deleterious product of genotoxic agents or radiotherapy. Despite the inherent chromatin localization of DSBs, the literature has largely ignored the effect of local chromatin or histone post translational modifications (PTMs) on DSB induction or recognition especially in a therapy-relevant setting. Analysis of epigenetic linkages to the DNA Damage Response are challenging owing to the random nature of exogenous DSB induction. Here, we directly measure stochastic DNA damage induced by ionizing radiation (IR) and infer relationships between basal epigenetic states and cellular ability to detect DSBs. Contrary to the expected uniform localization of DSBs and γH2AX, we show that DSB recognition is separate from DSB induction and that both processes are dependent on the local chromatin milieu. In general, actively transcribed regions contain more γH2AX than heterochromatic regions suggesting a link between transcription and the DDR. In contrast to previous studies, we suggest that transcription proximal to DNA damage is necessary for early DSB detection and suggest a requirement for transcription mediated repair in genome maintenance. Finally, we reveal a dual effect of the repressive mark H3K27me3 on the DNA damage response. While basal H3K27me3 attenuates γH2AX deposition, transcribed regions recruit H3K27me3 following DSB induction possibly as an obligate step in DSB recognition. We uncover epigenetic determinants of DSB recognition and suggest new mechanisms by which the epigenome direct DNA repair. Our findings suggest new targets for radio-adjuvant therapy and reframe the current stochastic model of radiotherapy induced damage.
2021-12-31 | GSE181934 | GEO
Project description:To reveal the involved gene regulatory pathways, we carried out RNA-seq transcriptomics analysis on the cells treated with or without PA, treated with PA+OA and PA+BMS.
2022-12-22 | GSE220856 | GEO
Project description:RNA-dependent RNA polymerase 6 (RDR6) is a core component of the small RNA biogenesis pathway, but its function in meiosis is unclear. Herein we report a new allele of OsRDR6 (Osrdr6-mei), which causes meiosis-specific phenotype in rice. In Osrdr6-mei, meiotic DSB formation was blocked to some extent. We further created a biallelic mutant, Osrdr6-bi, by crossing Osrdr6-mei with a knock out mutant, Osrdr6-edit (Osrdr6-edi). In Osrdr6-bi, 24 univalents were observed at diakinesis, and no histone H2AX phosphorylation (γH2AX) foci was detected in meiocytes, indicating that OsRDR6 is crucial for meiotic DSB formation. Compared with the wild type, the number of 21-nt small RNAs was dramatically reduced, while the number of 24-nt small RNAs was significantly increased in Osrdr6-mei. And thousands of DMRs discovered in Osrdr6-mei, implying that OsRDR6 plays an essential role on DNA methylation, especially CHH methylation. Meanwhile, the transcriptome data showed that 457 genes were down-regulated in the mutant; including three genes related to DSB formation: OsSDS, P31comet and CRC1. Interestingly, the increased 24-nt small RNA level surrounding down-regulated genes was largely associated with the silencing of these genes, while DMRs were rarely related to them. In summary, we speculated that the small RNA levels are disordered in Osrdr6 mutants, which may lead to the defection of DSB formation.
2021-06-05 | GSE151871 | GEO