Overview of the HERV-loci differentially expressed in SKOV3WT ovarian carcinoma cells treated with the HDACis romidepsin and vorinostat
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PROVIDER: PRJNA692113 | ENA |
REPOSITORIES: ENA
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Project description:To check the acetylation levels at the positions harbouring HERV-loci and assess their variation after the treatment with HDACis (Vorinostat, romidepsin), the univocal genomic coordinates of about 3280 HERV-loci have been compared with the position of the H3AcK9 peaks identified by ChIP-seq analysis. The first analysis confirmed that HDACis are able to modulate the acetylation of repetitive elements, including HERV sequences. Subsequently, we considered only the differential peaks (diffpeaks), i.e. the peaks showing significant variation after the treatment with vorinostat and/or romidepsin. Interestingly, even if more than half of HERV-loci co-localised with acetylation peaks after HDACi treatment, only a minority of them (0.9 to 1.9%) co-localised with diffpeaks, showing mostly a reduction in their acetylation levels. Diffpeaks co-localised HERV-loci could be classified into 24 HERV groups and included the ERV-V2 locus. We focused then on the 11 HERV-loci which co-localised with diffpeaks showing an increase in acetylation levels, hence indicating an increased transcriptional activation after HDACi treatment. Remarkably, diffpeaks corresponding to the ERV-V2 locus were identified in all samples and were the most significantly upregulated in both vorinostat and romidepsin treatment. This was in part confirmed by ChIP-qPCR in different OC cells. Beside ERV-V2, only the HML8 sequence at locus 2q11,2 showed increased acetylation levels in all treated samples, independent from the HDACis used, but having lower statistical significance. The analysis revealed that the treatment with HDACis did not only account for the significant increase of ERV-V2 acetylation, but also led to the shift and concentration of acetylation peaks at the 5’ region of the HERV provirus. This observation allows us to hypothesize that HDACi treatment could not only increase ERV-V2 transcriptional activation, but also modify its pattern of expression, and eventually leading to alternative splicing.
2021-01-15 | GSE164809 | GEO
Project description:Purpose: In an HIV cure setting, Vorinostat may provide the “shock” capable of flushing HIV out of the persistent reservoir, while antiretroviral therapy is used to prevent new infections. However, this drug may modulate the expression of human endogenous retroviruses (HERVs). This study demonstrates significant modulation of HERVs and suggests that they should be considered as off-target effects of this drug treatment. Methods: Peripheral blood mononuclear cells were collected from 4 healthy donors. Naive CD4 T cells were isolated and utilized to assess HERV dysregulation after treatment with Vorinostat. Cells were collected for study and exposed to a dose of Vorinostat (10uM dose over a 24 hour period). After this, RNA was extracted from cells and their untreated paired counterparts for deep sequencing by Expression Analysis. Sequence reads that passed quality filters were mapped to the HERVd reference database using Bowtie and counted using HTSeq. Any HERV which did not achieve at least 1 count per million mapped and counted reads in at least 4 samples was discarded. Differential expression was performed upon the filtered dataset with edgeR and using TMM normalization. Results: Using an custom built data analysis pipeline, ~100 million reads per sample were mapped to the HERVd reference database and identified 10784 distinct dysregulated elements Bowtie/HTSeq workflow. Differential expression analysis was performed between vorinostat treated and untreated conditions which demonstrated 2102 dysregulated HERV elements with 1007 downregulated and 1095 upregulated (FDR < 0.05) with EdgeR. Results were further subset with a log2FC ± 3 which resulted in 451 upregulated and 363 downregulated HERV elements from 81 and 82 distinct families respectively. HERV elements from the LTR12 family were by far the most dramatically upregulated in family frequency and fold change magnitude. Further confirmation with droplet digital PCR confirmed upregulation of LTR12 elements and demonstrated an exponential dose response curve with HERV expression found at even moderate doses (334nM) of vorinostat treatment. Conclusions: This study represents the first detailed analysis of HERV dysregulation following vorinostat treatment using the untargeted approach of total RNA-Seq. These results demonstrate that vorinostat dysregulates multiple HERV families with a propensity to upregulate members of the LTR12 HERV family. This study also provides a methodology to analyze HERV dysregulation in future treatments with vorinostat or other drugs by providing a mechanism to choose primer and probe sets which will properly represent HERV dysregulation as expression across an HERV is not uniform or continuous. Finally, this work suggests that HERV dysregulation by vorinostat treatment should be considered an off-target effect of this drug and HERV elements, such as LTR12, should be monitored as biomarkers during shock and kill clinical trials with HDAC inhibitors and that trial subjects should be screened to explore further HIV:HERV interactions.
2018-05-01 | GSE102187 | GEO
Project description:Colorectal cancer is one of the malignant tumors with the highest mortality rate in the world. Survival rates vary significantly among patients at various stages of the disease. A biomarker capable of early diagnosis is required to facilitate the early detection and treatment of colorectal cancer. Human endogenous retroviruses (HERVs) are abnormally expressed in various diseases, including cancer, and have been involved in cancer development. Real-time quantitative PCR was used to detect the transcript levels of HERV-K(HML-2) gag, pol, and env in colorectal cancer to systematically investigate the connection between HERV-K(HML-2) and colorectal cancer. The results showed that HERV-K(HML-2) transcript expression was significantly higher than healthy controls and was consistent at the population and cell levels. We also used next-generation sequencing to identify and characterize HERV-K(HML-2) loci that were differentially expressed between colorectal cancer patients and healthy individuals. The analysis revealed that these loci were concentrated in immune response signaling pathways, implying that HERV-K impacts the tumor-associated immune response. Our results indicated that HERV-K might serve as a screening tumor marker and a target for tumor immunotherapy in colorectal cancer.
| S-EPMC10277637 | biostudies-literature
Project description:The HERV-K(HML2) family is a group of elements of retroviral origin that are present in the human genome. They are silenced in most normal tissues, but are induced in a number of human cancers. In order to assess the relevance of their expression in these pathologies, the consequences of ectopic expression of the HERV-K(HML2) envelope protein were analysed in human 293T cells. The cells were transfected with a control vector, or an expression vector for the HERV-K(HML2) envelope protein. Total RNA was extracted 24h and 48h post transfection, and duplicate samples were analysed on whole genome transcriptional microarrays.
2017-06-17 | E-MTAB-5509 | biostudies-arrayexpress
Project description:Tamoxifen enhances romidepsin-induced senescence in pancreatic cancer cells. We compared gene-expression profile among untreated control, romidepsin-treated, tamoxifen-treated, and romidepsin plus tamoxifen-treated Panc1 cells.
2021-08-21 | GSE182526 | GEO
Project description:Potential vorinostat-resistance candidate genes were identified using RNA interference screening in vorinostat-resistant HCT116 cells (HCT116-VR) using a synthetic lethal approach. In order to understand the mechanisms by which these genes contributed to vorinostat response, transcriptomic analysis was conducted on HCT116-VR cells and those with siRNA-mediated knockdown of each of the vorinostat resistance candidate genes.
2014-07-07 | GSE56788 | GEO
Project description:Potential vorinostat-resistance candidate genes were identified using RNA interference screening in vorinostat-resistant HCT116 cells (HCT116-VR) using a synthetic lethal approach. In order to understand the mechanisms by which these genes contributed to vorinostat response, transcriptomic analysis was conducted on HCT116-VR cells and those with siRNA-mediated knockdown of each of the vorinostat resistance candidate genes. There are 45 samples in total, from triplicate independent biological experiments of 15 samples each. The negative control to which all gene knockdowns are compared is the mock transfection control (mock).
2014-07-07 | E-GEOD-56788 | biostudies-arrayexpress
Project description:Tamoxifen enhaces romidepsin-induced apoptosis in T-cell malignant cells. We compared gene-expression profile among untreated control, romidepsin-treted,
2020-02-21 | GSE145606 | GEO
Project description:ChIP-seq. analysis of TCam-2 16 h after 10 nanomolar Romidepsin application. DMSO treated cells were used as controls. For ChIP, an antibody against histone H3 pan-acetylation was used. These data are part of the article 'The Histone Deacetylase Inhibitor Romidepsin Efficiently Targets Cisplatin-resistant Germ Cell Cancer Cells via Downregulation of the SWI/SNF-Complex Member ARID1A' (Nettersheim et al., 2016). TCam-2 cells treated for 16h with romidepsin or the solvent were fixed by formaldehyde solution and further processed by Active Motif, including DNA shearing by sonication, chromatin-immunoprecipitaion, library generation and sequencing (NextSeq 500, Illumina). Pooled input DNA of each sample including spike-in Drosophila DNA was used as controls and for normalization. The 75-nt sequence reads were mapped against the genome using BWA algorithm. Duplicate reads were removed. Only peaks that align with no more than 2 mismatches and map uniquely to the genome were used for further analysis. Intervals / peaks were identified by the MACS peak finding algorithm (cutoff p-value 1x10-7) including ENCODE blacklist filtering
2016-09-01 | E-GEOD-78262 | biostudies-arrayexpress
Project description:Romidepsin displayed potent antitumor activity in our lenvatinib-resistant PDCs, we wanted to investigate the underlying mechanism of how romidepsin initiated susceptibility to conquer lenvatinib resistance in liver cancer.
2024-03-17 | GSE227751 | GEO