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RNA sequencing data from STS-109 human undifferentiated pleomorphic sarcoma (UPS) cells deficient in DNMT3A or DNMT3B expression

ABSTRACT: DNA methylation is frequently disrupted in sarcoma but little is known about the specific roles of DNA methyltransferases (DNMTs) in this process. Using an shRNA lentivirus-mediated genetic depletion approach, we found that reduction of DNMT3A or DNMT3B expression potently reduced UPS cell proliferation. Therefore, we performed RNA sequencing to identify global gene expression changes in DNMT3A- or DNMT3B-depleted cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200026 | GEO | 2022/10/03

REPOSITORIES: GEO

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Active DNA Demethylation by DNMT3A and DNMT3B - Mechanistic Aspect and In Vivo Evidence

Project description:The DNA methylation program is at the bottom layer of the epigenetic regulatory cascade of vertebrate development. While the methylation at C-5 position of the cytosine (C) residues on the vertebrate genomes is achieved through the catalytic activities of the DNA methyltransferases (DNMTs), the conversion of the methylated cytosine (5mC) could be accomplished by the combined actions of the TET enzyme and DNA repair. Interestingly, it has been found recently that the mouse and human DNMTs also possess active DNA demethylation activity in vitro in a Ca2+- and redox condition-dependent manner. We report here the study of tracking down the fate of the methyl group removed from 5mC on DNA during in vitro demethylation reaction by mouse de novo DNMTs, i.e. DNMT3A and DNMT3B. Remarkably, the methyl group becomes covalently linked to the catalytic cysteines utilized by the two de novo DNMTs in their DNA methylation reactions. Thus, the forward and reverse reactions of DNA methylations by the DNMTs may utilize the same cysteine residue(s) as the active site despite of their distinctive pathways. Secondly, we demonstrate that active DNA demethylation of a heavily methylated GFP reporter plasmid by ectopically expressed DNMT3A or DNMT3B occurs in vivo in transfected human HEK 293 cells in culture. Furthermore, the extent of DNA demethylation by the DNMTs in this cell-based system is affected by Ca2+ homeostasis as well as by mutation of their putative active cysteines. These findings substantiate the roles of the vertebrate DNMTs as double-edged swords in DNA methylation-demethylation in vitro as well as in a cellular context.

2022-02-24 | PXD003401 | Pride

RNA sequencing data from STS-109 human undifferentiated pleomorphic sarcoma (UPS) cells deficient in DNMT3A or DNMT3B expression

Project description:RNA sequencing data from STS-109 human undifferentiated pleomorphic sarcoma (UPS) cells deficient in DNMT3A or DNMT3B expression

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Gene expression profiles at single cell level of murine undifferentiated pleomorphic sarcoma (UPS)

Project description:We used scRNAseq to characterize the cell population diversity in UPS

2024-08-30 | GSE268865 | GEO

Gene expression signature from tumor initiating population predicts clinical outcome in undifferentiated pleomorphic sarcoma (UPS)

Project description:Undifferentiated pleomorphic sarcomas (UPS) are thought to harbor a small population of cells with unique capability of tumor initiation and maintenance. These tumor initiating cells (TICs) are regarded as the drivers of cancer progression. However, the evidence for this tumor initiating cell (TIC) concept is based on the xenotransplantation assays in mice and the clinical relevance of the TIC concept remains unclear in UPS. We hypothesized that the distinct properties of the TICs would be reflected in the clinical outcome if the TIC concept is relevant in UPS. Here we performed global gene expression profiling of TIC-enriched side population (SP) fractions and non-SP fractions sorted from 15 UPS primary samples. Ninety-three genes were differentially expressed in between SP fractions and non-SP fractions. The UPS TIC gene expression signature score summarizing expression of these genes was calculated for a gene expression data and was correlated with clinical outcome. In the 15 samples used to generate the signature, patients with high scores in the SP fractions were associated with worse survival. We then tested the two independent published datasets with gene expression data on bulk unsorted samples, assuming that the TIC gene expression would persist in the non-TICs. Patients with high scores had significantly worse metastasis-free survival in both datasets. The significance of the score remained significant even considering for the known prognostic factor of UPS. Thus, gene expression signature derived from UPS TICs predicts clinical outcome, suggesting the clinical relevance of the TIC concept in UPS.

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Dnmt3a and Dnmt3b-mediated decommissioning of fetal enhancers linked to kidney disease

Project description:Cytosine methylation is an epigenetic mark that dictates cell fate and response to stimuli. The timing and establishment of methylation logic during kidney development remains unknown. DNA methyltransferase 3a and 3b are the enzymes capable of establishing de novo methylation. We generated mice with genetic deletion of Dnmt3a and Dnmt3b in nephron progenitor cells (Six2Cre Dnmt3a/3b) and kidney tubule cells (KspCre Dnmt3a/3b). We characterized KspCre Dnmt3a/3b mice at baseline and after injury. Unbiased omics profiling, such as whole genome bisulfite sequencing, reduced representation bisulfite sequencing and RNA sequencing were performed on whole-kidney samples and isolated renal tubule cells. KspCre Dnmt3a/3b mice showed no obvious morphologic and functional alterations at baseline. Knockout animals exhibited increased resistance to cisplatin-induced kidney injury, but not to folic acid–induced fibrosis. Whole-genome bisulfite sequencing indicated that Dnmt3a and Dnmt3b play an important role in methylation of gene regulatory regions that act as fetal-specific enhancers in the developing kidney but are decommissioned in the mature kidney. Loss of Dnmt3a and Dnmt3b resulted in failure to silence developmental genes. We also found that fetal-enhancer regions methylated by Dnmt3a and Dnmt3b were enriched for kidney disease genetic risk loci. Methylation patterns of kidneys from patients with CKD showed defects similar to those in mice with Dnmt3a and Dnmt3b deletion. Our results indicate a potential locus-specific convergence of genetic, epigenetic, and developmental elements in kidney disease development.

2020-03-03 | GSE134267 | GEO

Effect of depletion of Setd1a on gene expression in mouse Undifferentiated Pleomorphic Sarcoma (UPS)

Project description:To investigate the Setd1a function in the regulation of lung metastasis formation, we established mouse UPS cell lines in which each target gene has been knocked down by shRNA. We then performed gene expression profiling analysis using data obtained from RNA-seq

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DNA methylation analysis and expression profiling during murine embryogenesis and in embryos deficient for DNMT3A or DNMT3B

Project description:We quantified the targets and kinetics of DNA methylation acquisition in mouse embryos, and determined the contribution of the de novo methyltransferases DNMT3A and DNMT3B to this process. We provide single-base maps of cytosine methylation by RRBS from the blastocysts to post-implantation stages and in embryos lacking DNMT3A or DNMT3B activity, and performed RNA-Seq in embryos lacking DNMT3B activity. We sequenced RRBS libraries prepared from genomic DNA isolated from embryos at consecutive stages of development between E3.5 and E11.5,and adult differentiated cells (sperm, liver). We performed RRBS on blastocysts at E3.5/E4.5, dissected epiblasts at E5.5/E6.5/E7/5, whole embryos at E8.5/E10.5 and limbs at E11.5. RRBS experiments in Dnmt3a-/- and Dnmt3b-/- embryos were performed in biological duplicates on individual embryos. We sequenced RNA-Seq libraries prepared from total RNAs of three WT and Dnmt3b-/- littermate embryos collected at E8.5.

2014-11-14 | E-GEOD-60334 | biostudies-arrayexpress

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2024-10-21 | GSE240786 | GEO

Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms

Project description:Mammalian DNA methylation patterns are established by two de novo DNA methyltransferases DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterizations of DNMT3A and DNMT3B, here we uncovered distinct and interrelated modes-of-action underlying their CpG site and flanking sequence interaction. Strikingly, K777 of DNMT3B makes direct contacts with the DNA base at the +1 flank position of the cytosine methylation site, which contrasts with its counterpart in DNMT3A that forms base-specific contacts with the CpG site. Consequently, there is a divergent substrate and flanking sequence preference between DNMT3A and DNMT3B in vitro and in cells, thus providing an explanation for site-specific epigenomic alterations seen in ICF syndrome patients with DNMT3B mutations. Together, this study reveals crucial, yet complicated interplays of DNMT3s, DNA sequences and resultant methylation.

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Gene expression profile of Dnmt1 flox/flox, Dnmt3a flox/flox, Dnmt3b flox/flox, cre negative (Wild type) and Dnmt1 flox/flox, Dnmt3a flox/flox, Dnmt3b flox/flox, Rx-cre (Triple mutant) murine retina transcriptomes

Project description:Purpose: The goal of this study was to identify the gene expression profile of mouse retina which carries deletions in Dnmt1, Dnmt3a and Dnmt3b genes. Method: Retinal mRNA profiles of Postnatal day 15 wild type mice and Dnmt1, Dnmt3a and Dnmt3b mutant mice were generated by deep-sequencing

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