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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Adenovirus E1A oncogene induces re-replication of cellular DNA and alters DNA replication dynamics

ABSTRACT: Human adenovirus type 5 oncogene E1A was shown to induce massive re-replication of cellular DNA in late S phase. Using DNA combing analysis, it was shown that DNA replication dynamics including replicon length, fork velocity and inter-origin distance were dramatically altered in E1A expressing cells as compared to that of normal serum stimulated cells. It was also shown that c-Myc that is induced in E1A expressing cells is essential for the efficient entry of E1A expressing cells into S phase. Serum starved cells were infected with an adenovirus expressing only the transforming E1A protein, and with Adbeta-galactosidase (control) were analyzed by flow cytomery. DNA prepared from such cells were analyzed by DNA combing analysis and data obtained were examined statistically. Requirement of Myc in E1A induced S phase entry was also examined by using antisense Myc vector.

ORGANISM(S): Homo sapiens

SUBMITTER: Ghata Singhal

PROVIDER: E-GEOD-47140 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Adenovirus E1A oncogene induces re-replication of cellular DNA and alters DNA replication dynamics

Project description:Human adenovirus type 5 oncogene E1A was shown to induce massive re-replication of cellular DNA in late S phase. Using DNA combing analysis, it was shown that DNA replication dynamics including replicon length, fork velocity and inter-origin distance were dramatically altered in E1A expressing cells as compared to that of normal serum stimulated cells. It was also shown that c-Myc that is induced in E1A expressing cells is essential for the efficient entry of E1A expressing cells into S phase.

2013-05-22 | GSE47140 | GEO

Gene expression profile of E1A infected C2C12 myotubes

Project description:Proliferating C2C12 myoblasts were induced to differentiate into myotubes and then infected with adenovirus expressing E1A (Ad-E1A), which induces cell cycle re-entry and dedifferentiation. We analyzed the transcriptional profile of E1A infected C2C12-myotubes through the Affymetrix Mouse Genome 430 2.0 Array, searching for genes that were significantly regulated between two independent biological replicates at two different time points (24h and 36h after infection with Ad-E1A). In addition, we took advantage of the E1A mutant known as YH47/dl928 (hereafter referred as YH47), which bears two mutations in the pocket-binding region of E1A (Y48H, C124G) able to disrupt the interaction with Rb and its cognate proteins and to impair cell-cycle re-entry phenotype. YH47 mutant was used to identify the Rb independent transcriptional reprogramming of C2C12. C2C12 cells were differentiated in vitro to myotubes as previously described. Myotubes were, then, infected with an adenovirus carrying the 12S form of E1A (dl520), with the YH47 E1A mutant (dl928) or with a control adenovirus (CTR) expressing a deletion of essentially the entire E1A gene (dl312). Two different time points after infection were considered (24 hours and 36 hours) to evaluate changes in C2C12 cells expression profile. Technical (A or B) and biological replicates (EXP1 or EXP2) were done for each condition.

2012-05-30 | E-GEOD-28457 | biostudies-arrayexpress

Gene expression profile of E1A infected C2C12 myotubes

2012-05-31 | GSE28457 | GEO

The cohesin complex prevents Myc-induced replication stress

Project description:The cohesin complex is mutated in cancer and in a number of rare familiar syndromes collectively known as Cohesinopathies. In the latter case, cohesin deficiencies have been linked to transcriptional alterations affecting Myc and its target genes. Here, we set out to understand to what extent the role of cohesins in controlling cell cycle is dependent on Myc expression and activity. Inactivation of the cohesin complex by silencing the RAD21 subunit led to cell cycle arrest due to both transcriptional impairment of Myc target genes and alterations of replication forks, which were fewer and preferentially unidirectional. Ectopic activation of Myc in RAD21 depleted cells, fully rescued transcription and promoted S-phase entry but failed to sustain S-phase progression thus leading to a strong replicative stress response, which was associated to a robust DNA damage response, DNA damage checkpoint activation and synthetic lethality. Thus, the cohesin complex is dispensable for Myc dependent transcription but essential to prevent Myc induced replicative stress. This suggests the presence of a topological checkpoint orchestrated by cohesins that by regulating Myc level prevents S-phase entry and replicative stress in cohesion compromised cells.

2017-12-22 | GSE89799 | GEO

Screening of new target genes specifically activated by deregulated E2F

Project description:To identify genes specifically activated by deregulated E2F, we examined gene expression profiles using human normal fibroblasts (HFFs), which were starved of serum and re-stimulated with serum, over-expressed with E2F1 or expressed with adenovirus E1a to forcedly inactivate RB. To identify genes activated by growth stimulation, human normal fibroblasts (HFFs) were starved of serum for 48 hr, infected with control virus, restimulated with serum or left serum-starved for 18 hr and harvested. To identify genes actived by deregulated E2F, HFFs were starved of serum for 48 hr, infected with control virus, adenovirus expressing E2F1 or adenovirus E1a, further cultured in the absence of serum for 18 hr and harvested. Gene expression profiles of ecach sample were examined by DNA microarray.

2015-11-20 | E-GEOD-67887 | biostudies-arrayexpress

The Adenovirus E1A C Terminus Suppresses a Delayed Antiviral Response and Modulates RAS Signaling [Pol2_H3K18ac_H3K27ac_ChIP]

Project description:The N-terminal half of adenovirus e1a assembles multimeric complexes with host proteins that repress innate immune responses and force host cells into S-phase. In contrast, the functions of e1a's C-terminal interactions with FOXK, DCAF7, and CtBP are unknown. We found that these interactions modulate RAS signaling, and that a single e1a molecule must bind all three of these host proteins to suppress activation of a subset of IFN-stimulated genes (ISGs). These ISGs were otherwise induced in primary respiratory epithelial cells at 12 hr p.i. This delayed activation of ISGs required IRF3 and coincided with an ∼10-fold increase in IRF3 from protein stabilization. The induced IRF3 bound to chromatin and localized to the promoters of activated ISGs. While IRF3, STAT1/2, and IRF9 all greatly increased in concentration, there were no corresponding mRNA increases, suggesting that e1a regulates the stabilities of these key activators of innate immune responses, as shown directly for IRF3.

2017-12-13 | GSE105038 | GEO

The Adenovirus E1A C Terminus Suppresses a Delayed Antiviral Response and Modulates RAS Signaling [IRF3_ChIP]

2017-12-13 | GSE105037 | GEO

The Adenovirus E1A C Terminus Suppresses a Delayed Antiviral Response and Modulates RAS Signaling [RNA-seq]

2017-12-13 | GSE105039 | GEO

Expression profiles and ChIP on chip genomewide experiments with dl1500 virus (expressing WT small e1a).

Project description:Adenovirus e1a induces quiescent human cells to divide. We found that e1a causes global relocalization of the RB-proteins (RB, p130, p107) and p300/CBP histone acetyltransferases on promoters that restricts H3K18ac to a limited set of genes to stimulate cell cycling and inhibit antiviral responses and cellular differentiation. Soon after expression, e1a binds transiently to cell cycle/growth genes, causing enrichment of p300/CBP, PCAF, H3K18ac, depletion of RB-proteins, and transcriptional activation. e1a also associates transiently with antiviral genes, causing enrichment for RB, p130, H4K16ac, increased nucleosome density, and repression. At later times, e1a and p107 bind mainly to development/differentiation genes, repressing transcription. The temporal order of e1a binding required its interactions with p300/CBP and RB-proteins. Our data uncover a defined transcriptional and epigenetic reprogramming leading to cellular transformation. Expression profiles and ChIP on chip genomewide experiments with dl1500 virus (expressing WT small e1a).

2008-08-26 | E-GEOD-12045 | biostudies-arrayexpress

CBP/P300 Function in Repression as well as Activation Regulated by Adenovirus Small E1A [RNA-seq]

Project description:Oncogenic transformation by adenovirus small e1a depends on simultaneous interactions with P300/CBP and RB proteins. To understand why, experiments with structure-based e1a mutants were analyzed with RNA- and ChIP-seq. The results indicate that e1a displaces RBs from E2F activation domains and, by promoting P300 acetylation of RB1 K873/K874, locks them into a repressing conformation that interacts with repressive chromatin modifying enzymes. e1a then delivers these repressing p300-e1a-RB1 complexes to cell genes that have unusually high P300 association with the gene body, enriched in genes of the TGFb-, TNF-, and IL1-signaling pathways. The P300-e1a-RB complex condenses chromatin, dependent on HDAC activity, P300 lysine acetylase activity, the P300 bromodomain, and acetylation of RB K873/K874 and e1a K239, contributing to repression of host genes that would otherwise inhibit cell cycling. The data suggest why e1a must bind P300/CBP as well as RBs for oncogenic transformation and why a trimeric P300-e1a-RB1 complex is required. Examination of transcriptome by mRNA sequencing before and after infection by adenoviral e1a expressing vectors in growth arrested IMR90

2014-08-15 | E-GEOD-59688 | biostudies-arrayexpress

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