Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA353659 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5024390_1.fastq.gz | Fastqsanger.gz | |||
| SRR5024390_2.fastq.gz | Fastqsanger.gz | |||
| SRR5024391_1.fastq.gz | Fastqsanger.gz | |||
| SRR5024391_2.fastq.gz | Fastqsanger.gz | |||
| SRR5024392_1.fastq.gz | Fastqsanger.gz |
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Project description:DNA breaks and chromatin structural changes enhance the transcription of Autoimmune Regulator target genes
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Project description:DNA breaks and chromatin structural changes enhance the transcription of Autoimmune Regulator target genes [RNA-Seq]
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Project description:The Autoimmune Regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T-cells by promoting the ectopic expression of tissue-specific genes in thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA-seq, we found that the inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by topoisomerase 1 (TOP1) inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional upregulation to co-occur with the chromatin structural changes within the genomic cluster of carcino-embryonic antigen-like cellular adhesion molecule (CEACAM) genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes.
2017-03-13 | GSE76240 | GEO
Project description:The Autoimmune Regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T-cells by promoting the ectopic expression of tissue-specific genes in thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA-seq, we found that the inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by topoisomerase 1 (TOP1) inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional upregulation to co-occur with the chromatin structural changes within the genomic cluster of carcino-embryonic antigen-like cellular adhesion molecule (CEACAM) genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes.
2017-03-13 | GSE89892 | GEO
Project description:Many anti-cancer drugs induce DNA breaks to eliminate tumor cells. The anthracycline topoisomerase II inhibitors can also evict histones. We performed a genome-wide high-resolution mapping of chemotherapeutic effects of various topoisomerase I and II inhibitors. We show that different drugs target different types of chromatin for induction of DNA damage and histone eviction. Topoisomerase inhibitors topotecan and etoposide similarly target transcriptionally active chromatin for DNA damage. Daunorubicin induces DNA breaks and evicts histones in active chromatin, thus quenching local DNA damage response. The analog aclarubicin evicts histones in H3K27me3-marked heterochromatin. These results can guide rational treatment decisions regarding these genome manipulating anti-cancer drugs. FAIRE-seq and g-H2AX ChIP-seq were performed on K562 cells after drug exposure
2015-05-10 | E-GEOD-60395 | biostudies-arrayexpress
Project description:The eukaryotic genome is organized into chromatins, the physiological template for DNA-dependent processes including replication, recombination, repair, and transcription. Chromatin-mediated transcription regulation involves DNA methylation, chromatin remodeling, and histone modifications. However, chromatin also contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Although it is known that HMG proteins induce structural changes of chromatin, the processes underlying transcription regulation by HMG proteins are poorly understood. Here we decipher the molecular mechanism of transcription regulation mediated by the HMG AT-hook 2 protein (HMGA2). We combined proteomic, ChIP-seq, and transcriptome data to show that HMGA2-induced transcription requires phosphorylation of the histone variant H2AX at S139 (H2AXS139ph; γ-H2AX) mediated by the protein kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrate the biological relevance of this mechanism within the context of TGFβ1 signaling. The interplay between HMGA2, ATM, and H2AX is a novel mechanism of transcription initiation. Our results link H2AXS139ph to transcription, assigning a new function for this DNA damage marker. Controlled chromatin opening during transcription may involve intermediates with DNA breaks that may require mechanisms that ensure the integrity of the genome.
2020-12-15 | PXD016586 | Pride
Project description:A1-2 cells treated with 100 nM Dexamethasone or ethanol vehicle for 8h. The ability of steroid hormone receptors to initiate a genetic program is tightly regulated by the chromatin environment of the responsive regions. Using the glucocorticoid receptor (GR) as a model factor for transcriptional initiation, we classified chromatin structure through Formaldehyde Assisted Isolation of Regulatory Elements (FAIRE), a technique designed to identify regulatory regions and open chromatin within the genome. We looked at dynamic changes in FAIRE signals prior to and following activation of GR with its ligand, dexamethesone, specifically at regions of receptor interaction. We have found a distribution of GR responsive regions that respond to activation by varying degrees of chromatin modulation. The majority of regions that demonstrate GR interaction also demonstrate increases in FAIRE signal in response to ligand. Most of these GR responsive regions fell within a narrow window of FAIRE signal in the basal chromatin state, suggesting a preferred chromatin structure for GR recruitment. Supporting this notion, global FAIRE-seq data indicated an enrichment of signal surrounding the GR binding site prior to activation. FAIRE signal induction correlated to an increase in nuclease sensitivity and overall FAIRE signal also represented a general accessibility of the chromatin. Further investigation into the requirement of ATPase-dependent chromatin remodeling showed response element specific effects of Brg-1 knockdown. FAIRE induction was universally decreased by Brg-1 depletion, but to varying degrees in a target specific manner. Taken together, these data suggest classes of nuclear receptor response regions that react to activation through different chromatin regulatory events and identify a novel identifier of chromatin structure that classifies the majority of response elements tested.
2012-02-28 | GSE30592 | GEO
Project description:A1-2 cells treated with 100 nM Dexamethasone or ethanol vehicle for 8h. The ability of steroid hormone receptors to initiate a genetic program is tightly regulated by the chromatin environment of the responsive regions. Using the glucocorticoid receptor (GR) as a model factor for transcriptional initiation, we classified chromatin structure through Formaldehyde Assisted Isolation of Regulatory Elements (FAIRE), a technique designed to identify regulatory regions and open chromatin within the genome. We looked at dynamic changes in FAIRE signals prior to and following activation of GR with its ligand, dexamethesone, specifically at regions of receptor interaction. We have found a distribution of GR responsive regions that respond to activation by varying degrees of chromatin modulation. The majority of regions that demonstrate GR interaction also demonstrate increases in FAIRE signal in response to ligand. Most of these GR responsive regions fell within a narrow window of FAIRE signal in the basal chromatin state, suggesting a preferred chromatin structure for GR recruitment. Supporting this notion, global FAIRE-seq data indicated an enrichment of signal surrounding the GR binding site prior to activation. FAIRE signal induction correlated to an increase in nuclease sensitivity and overall FAIRE signal also represented a general accessibility of the chromatin. Further investigation into the requirement of ATPase-dependent chromatin remodeling showed response element specific effects of Brg-1 knockdown. FAIRE induction was universally decreased by Brg-1 depletion, but to varying degrees in a target specific manner. Taken together, these data suggest classes of nuclear receptor response regions that react to activation through different chromatin regulatory events and identify a novel identifier of chromatin structure that classifies the majority of response elements tested. Experiment performed in triplicate. 3 biological replicates of A1-2 cells treated with dexamethasone and 3 biological replicates of A1-2 cells treated with ethanol
2012-02-28 | E-GEOD-30592 | biostudies-arrayexpress
Project description:The ability of chromatin to switch back and forth from open euchromatin to closed heterochromatin is vital for transcriptional regulation and genomic stability, and subject to disruption by exposure to environmental agents such as hexavalent chromium. Cr(VI) exposure can cause chromosomal disruption through formation of Cr-DNA adducts, free radical-induced DNA damage, and DNA-Cr-protein and DNA-Cr-DNA cross-links, all of which may disrupt chromatin remodeling mechanisms responsible for maintenance or controlled modification of epigenetic homeostasis. In addition, dose-response analyses have shown that acute exposures to high-concentrations of Cr(VI) and chronic exposures to low-concentrations of the same agent lead to significantly different transcriptomic and genomic stability outcomes. To investigate how transcriptional responses to chromium exposure might correlate to structural changes in chromatin, we have used whole genome Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE) analysis coupled with deep sequencing to identify regions of the genome that switch from open to closed chromatin or vice versa in response to exposure to varying Cr(VI) concentrations. We find that the switch affects gene expression levels in the target areas that vary depending on Cr(VI) concentration. At either Cr(VI) concentration, chromatin domains surrounding binding sites for AP-1 transcription factors become significantly open, treatment whereas BACH2 and CTCF binding sites are open solely at the low and high concentrations, respectively. Our results suggest that FAIRE may be a useful technique to map chromatin elements targeted by DNA damaging agents for which there is no prior knowledge of their specificity, and to identify subsequent transcriptomic changes induced by those agents.
2014-04-10 | GSE56636 | GEO
Project description:Genomic enhancers regulate spatio-temporal gene expression by recruiting specific combinations of transcription factors (TFs). When TFs are bound to active regulatory regions, they displace canonical nucleosomes, making these regions biochemically detectable as nucleosome-depleted regions or accessible/open chromatin. Here we ask whether open chromatin profiling can be used to identify the entire repertoire of active promoters and enhancers underlying tissue-specific gene expression during normal development and oncogenesis in vivo. To this end, we first compare two different approaches to detect open chromatin in vivo using the Drosophila eye primordium as a model system: FAIRE-seq, based on physical separation of open versus closed chromatin; and ATAC-seq, based on preferential integration of a transposon into open chromatin. We find that both methods reproducibly capture the tissue-specific chromatin activity of regulatory regions, including promoters, enhancers, and insulators. Using both techniques, we screened for regulatory regions that become ectopically active during Ras-dependent oncogenesis, and identified 3778 regions that become (over-)activated during tumor development. Next, we applied motif discovery to search for candidate transcription factors that could bind these regions and identified AP-1 and Stat92E as key regulators. We validated the importance of Stat92E in the development of the tumors by introducing a loss of function Stat92E mutant, which was sufficient to rescue the tumor phenotype. Additionally we tested if the predicted Stat92E responsive regulatory regions are genuine, using ectopic induction of JAK/STAT signaling in developing eye discs, and observed that similar chromatin changes indeed occurred. Finally, we determine that these are functionally significant regulatory changes, as nearby target genes are up- or down-regulated. In conclusion, we show that FAIRE-seq and ATAC-seq based open chromatin profiling, combined with motif discovery, is a straightforward approach to identify functional genomic regulatory regions, master regulators, and gene regulatory networks controlling complex in vivo processes. FAIRE-Seq in Drosophila wild type eye-antennal imaginal discs (2 wt strains); ATAC-Seq in Drosophila wild type eye-antennal imaginal discs (3 wt strains) ; FAIRE-Seq in Drosophila Ras/Scrib induced eye disc tumors (1 early and 1 late); ATAC-Seq in Drosophila Ras/Scrib induced eye disc tumors (1 early and 1 late); ATAC-Seq in Drosophila eye discs with Unpaired over-expression (2 biological replicates); CTCF ChIP-seq in Drosophila eye discs; ChIP-seq input in Drosophila eye discs
2015-02-13 | E-GEOD-59078 | biostudies-arrayexpress