Similar Datasets
Project description:Transposable elements (TE) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression increases in a wide range of cancers and is correlated with global hypomethylation of cancer genomes. We assessed expression and DNA methylation of TEs in fibroblast cells that were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, modeling the different steps of the tumorigenesis process. RNA sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation. TE expression significantly increased as cells progressed through transformation, with the largest increase in expression after the final stage of transformation, consistent with data from human tumors. The upregulated TEs were dominated by endogenous retroviruses [long terminal repeats (LTR)]. Most differentially methylated regions (DMR) in all stages were hypomethylated, with the greatest hypomethylation in the final stage of transformation. A majority of the DMRs overlapped TEs from the RepeatMasker database, indicating that TEs are preferentially demethylated. Many hypomethylated TEs displayed a concordant increase in expression. Demethylation began during immortalization and continued into transformation, while upregulation of TE transcription occurred in transformation. Numerous LTR elements upregulated in the model were also identified in The Cancer Genome Atlas datasets of breast, colon, and prostate cancer. Overall, these findings indicate that TEs, specifically endogenous retroviruses, are demethylated and transcribed during transformation.SignificanceAnalysis of epigenetic and transcriptional changes in a transformation model reveals that transposable element expression and methylation are dysregulated during oncogenic transformation.
| S-EPMC10527578 | biostudies-literature
Project description:Transposable elements (TEs) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression increases in a wide range of cancers and is correlated with global hypomethylation of cancer genomes. We assessed expression and DNA methylation of TEs in fibroblast cells that were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, which models the different steps of the tumorigenesis process. RNA-sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation. TE expression significantly increased as cells progressed through transformation, with the largest increase in expression after the final stage of transformation, consistent with data from human tumors. The upregulated TEs were dominated by endogenous retroviruses (LTRs). Most differentially methylated regions (DMRs) in all stages were hypomethylated, with the greatest hypomethylation in the final stage of transformation. A majority of the DMRs overlapped TEs from the RepeatMasker database, indicating that TEs are preferentially demethylated. Many hypomethylated TEs displayed a concordant increase in expression. Demethylation began during immortalization and continued into transformation, while upregulation of TE transcription occurred in transformation. Numerous LTR elements upregulated in the model were also identified in TCGA datasets of breast, colon, and prostate cancer. Overall, these findings indicate that transposable elements, specifically endogenous retroviruses, are demethylated and transcribed during transformation.
2023-06-28 | GSE231778 | GEO
Project description:Malignant Transformation Drives DNA Methylation Loss and Transcriptional Activation of Transposable Element Loci
| PRJNA967669 | ENA
Project description:Malignant Transformation Drives DNA Methylation Loss and Transcriptional Activation of Transposable Element Loci [WGBS]
| PRJNA967674 | ENA
Project description:Multicellular eukaryotic genomes show enormous differences in size. A substantial part of this variation is due to the presence of transposable elements (TEs). They contribute significantly to a cell's mass of DNA and have the potential to become involved in host gene control. We argue that the suppression of their activities by methylation of the C-phosphate-G (CpG) dinucleotide in DNA is essential for their long-term accommodation in the host genome and, therefore, to its expansion. An inevitable consequence of cytosine methylation is an increase in C-to-T transition mutations via deamination, which causes CpG loss. Cytosine deamination is often needed for TEs to take on regulatory functions in the host genome. Our study of the whole-genome sequences of 53 organisms showed a positive correlation between the size of a genome and the percentage of TEs it contains, as well as a negative correlation between size and the CpG observed/expected (O/E) ratio in both TEs and the host DNA. TEs are seldom found at promoters and transcription start sites, but they are found more at enhancers, particularly after they have accumulated C-to-T and other mutations. Therefore, the methylation of TE DNA allows for genome expansion and also leads to new opportunities for gene control by TE-based regulatory sites.
| S-EPMC7431005 | biostudies-literature
Project description:Meningiomas are central nervous system tumors that originate from the meningeal coverings of the brain and spinal cord. Most meningiomas are pathologically benign or atypical, but 3-5% display malignant features. Despite previous studies on benign and atypical meningiomas, the key molecular pathways involved in malignant transformation remain to be determined, as does the extent of epigenetic alteration in malignant meningiomas. In this study, we explored the landscape of DNA methylation in ten benign, five atypical and four malignant meningiomas. Compared to the benign tumors, the atypical and malignant meningiomas demonstrate increased global DNA hypomethylation. Clustering analysis readily separates malignant from atypical and benign tumors, implicating that DNA methylation patterns may serve as diagnostic biomarkers for malignancy. Genes with hypermethylated CpG islands in malignant meningiomas (such as HOXA6 and HOXA9) tend to coincide with the binding sites of polycomb repressive complexes (PRC) in early developmental stages. Most genes with hypermethylated CpG islands at promoters are suppressed in malignant and benign meningiomas, suggesting the switching of gene silencing machinery from PRC binding to DNA methylation in malignant meningiomas. One exception is the MAL2 gene that is highly expressed in benign group and silenced in malignant group, representing de novo gene silencing induced by DNA methylation. In summary, our results suggest that malignant meningiomas have distinct DNA methylation patterns compared to their benign and atypical counterparts, and that the differentially methylated genes may serve as diagnostic biomarkers or candidate causal genes for malignant transformation.
| S-EPMC3551961 | biostudies-literature
Project description:Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1-/- SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.
| S-EPMC6687955 | biostudies-literature
Project description:Mesenchymal transformation is a hallmark of aggressive glioblastoma (GBM). Here, we report the development of an unbiased method for computational integration of copy number variation, expression, and mutation data from large datasets. Using this method, we identified rhophilin 2 (RHPN2) as a central genetic determinant of the mesenchymal phenotype of human GBM. Notably, amplification of the human RHPN2 gene on chromosome 19 correlates with a dramatic decrease in the survival of patients with glioma. Ectopic expression of RHPN2 in neural stem cells and astrocytes triggered the expression of mesenchymal genes and promoted an invasive phenotype without impacting cell proliferation. Mechanistically, these effects were implemented through RHPN2-mediated activation of RhoA, a master regulator of cell migration and invasion. Our results define RHPN2 amplification as a central genetic determinant of a highly aggressive phenotype that directs the worst clinical outcomes in patients with GBM.
| S-EPMC3805507 | biostudies-literature
Project description:DNA methylation and epigenetic silencing play important roles in the regulation of transposable elements (TEs) in many eukaryotic genomes. A majority of the maize genome is derived from TEs that can be classified into different orders and families based on their mechanism of transposition and sequence similarity, respectively. TEs themselves are highly methylated and it can be tempting to view them as a single uniform group. However, the analysis of DNA methylation profiles in flanking regions provides evidence for distinct groups of chromatin properties at different TE families. These differences among TE families are reproducible in different tissues and different inbred lines. TE families with varying levels of DNA methylation in flanking regions also show distinct patterns of chromatin accessibility and modifications within the TEs. The differences in the patterns of DNA methylation flanking TE families arise from a combination of non-random insertion preferences of TE families, changes in DNA methylation triggered by the insertion of the TE and subsequent selection pressure. A set of nearly 70,000 TE polymorphisms among four assembled maize genomes were used to monitor the level of DNA methylation at haplotypes with and without the TE insertions. In many cases, TE families with high levels of DNA methylation in flanking sequence are enriched for insertions into highly methylated regions. The majority of the >2,500 TE insertions into unmethylated regions result in changes in DNA methylation in haplotypes with the TE, suggesting the widespread potential for TE insertions to condition altered methylation in conserved regions of the genome. This study highlights the interplay between TEs and the methylome of a major crop species.
| S-EPMC6752859 | biostudies-literature
Project description:The liver possesses extraordinary regenerative capacity mainly attributable to the ability of hepatocytes (HCs) and biliary epithelial cells (BECs) to self-replicate. This ability is left over from their bipotent parent cell, the hepatoblast, during development. When this innate regeneration is compromised due to the absence of proliferative parenchymal cells, such as during cirrhosis, HCs and BEC can transdifferentiate; thus, adding another layer of complexity to the process of liver repair. In addition, dysregulated lineage maintenance in these two cell populations has been shown to promote malignant growth in experimental conditions. Here, malignant transformation, driven in part by insufficient maintenance of lineage reprogramming, contributes to end-stage liver disease. Epigenetic changes are key drivers for cell fate decisions as well as transformation by finetuning overall transcription and gene expression. In this review, we address how altered DNA methylation contributes to the initiation and progression of hepatic cell fate conversion and cancer formation. We also discussed the diagnostic and therapeutic potential of targeting DNA methylation in liver cancer, its current limitations, and what future research is necessary to facilitate its contribution to clinical translation.
| S-EPMC9841769 | biostudies-literature