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Project description:Occupancy-based Mechanism Is the Chief Mode of ROS1 Function in Preventing DNA Hypermethylation
| PRJNA1186947 | ENA
Project description:DNA methylation patterning is a consequence of opposing activities of DNA methyltransferases and DNA demethylases. In many species, reproduction is a period of significant epigenome lability. In flowering plants, two distinct female gametes, the egg cell and the central cell, are fertilized, producing the embryo and the endosperm, respectively, of the seed. The endosperm is an unusual tissue, exemplified by triploidy and reduced DNA methylation. In Arabidopsis thaliana, a 5-methylcytosine DNA glycosylase, DME, demethylates regions in the central cell genome, leading to methylation differences between maternally- and paternally-inherited endosperm genomes after fertilization. Expression of DME in the central cell is required for gene imprinting, or parent-of-origin specific gene expression, in endosperm. DME is part of a four member gene family in Arabidopsis that includes ROS1, DML2 and DML3. It is unknown whether any of the other DNA glycosylases are required for endosperm methylation patterning. Using whole-genome methylation profiling, we identify ROS1 target regions in the endosperm. We show that ROS1 prevents hypermethylation of paternally-inherited alleles in the endosperm at regions that lack maternal or paternal-allele methylation in wild-type. Thus, ROS1 promotes epigenetic symmetry between parental genomes in the endosperm by preventing paternal genome hypermethylation. We propose that ROS1 and DME act in a parent-of-origin-specific manner at shared endosperm targets, and consider possible implications for the evolution of imprinting mechanisms.
2025-03-28 | GSE280598 | GEO
Project description:Mitochondrial DNA (mtDNA) encodes for proteins required for oxidative phosphorylation, and mutations affecting the genome have been linked to a number of diseases as well as the natural ageing process in mammals. Human mtDNA is replicated by a molecular machinery that is distinct from the nuclear replisome, but there is still no consensus on the exact mode of mtDNA replication. We here demonstrate that the mitochondrial single-stranded DNA binding protein (mtSSB) directs origin specific initiation of mtDNA replication. MtSSB covers the parental heavy strand, which is displaced during mtDNA replication. MtSSB blocks primer synthesis on the displaced strand and restricts initiation of light-strand mtDNA synthesis to the specific origin of light-strand DNA synthesis (OriL). The in vivo occupancy profile of mtSSB displays a distinct pattern, with the highest levels of mtSSB close to the mitochondrial control region and with a gradual decline towards OriL. The pattern correlates with the replication products expected for the strand displacement mode of mtDNA synthesis, lending strong in vivo support for this debated model for mitochondrial DNA replication.
| S-EPMC4256270 | biostudies-literature
Project description:Hypermethylation of tumour suppressors and other aberrations of DNA methylation in tumours play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions, including hypoxia. The response to hypoxia is mainly achieved through activation of the transcriptional program associated with HIF1A transcription factor. Inactivation of Von Hippel-Lindau Tumour Suppressor gene (VHL) by genetic or epigenetic events, which also induces aberrant activation of HIF1A, is the most common driver event for renal cancer. With whole-genome bisulphite sequencing and LC-MS, we demonstrated that VHL inactivation induced global genome hypermethylation in human kidney cancer cells under normoxic conditions. This effect was reverted by exogenous expression of wild-type VHL. We showed that global genome hypermethylation in VHL mutants can be explained by transcriptional changes in MDH and L2HGDH genes that cause the accumulation of 2-hydroxyglutarate - a metabolite that inhibits DNA demethylation by TET enzymes. Unlike the known cases of DNA hypermethylation in cancer, 2-hydroxyglutarate was accumulated in the cells with the wild-type isocitrate dehydrogenases.
| S-EPMC9423849 | biostudies-literature
Project description:ObjectiveCellular repressor of E1A-stimulated genes (CREG), a vasculoprotective molecule, is significantly downregulated in atherosclerotic vessels through unclear mechanisms. While epigenetic regulation is involved in atherosclerosis development, it is not known if the CREG gene is epigenetically regulated. The aim of this study was to assess the potential role of CREG methylation in contributing to atherosclerosis.Approach and resultsOverexpression of DNA methyltransferase (DNMT)3B significantly inhibited CREG expression in human umbilical vein endothelial cells (HUVECs) and human coronary aortic endothelial cells (HCAECs).Conversely, inhibition of DNA methylation with 5-aza-2'-deoxycytidine (5-aza-dC) dose-dependently increased CREG expression. A CREG promoter analysis identified +168 to +255 bp as a key regulatory region and the CG site at +201/+202 bp as a key methylation site. The transcription factor GR-α could bind to the +201/+202 bp CG site promoting CREG transcription, a process significantly inhibited by DNMT3B overexpression. Treatment of cells with oxidized low-density lipoprotein (ox-LDL), a critical atherosclerogenic factor, significantly increased DNMT3B expression, increasing CREG promotor methylation, blocking GR-α binding, and inhibiting CREG expression. Consistently, CG sites in the CREG promoter fragment were hyper-methylated in human atherosclerotic arteries, and CREG expression was significantly reduced. A negative correlation between DNMT3B and CREG expression levels was observed in human atherosclerotic arteries. Finally, Ox-LDL-induced endothelium dysfunction was significantly attenuated by both 5-aza-dC and an anti-oxidative molecular N-acetylcysteine (NAC) administration through rescue the expression of CREG and activation of the p-eNOS/NO pathway.ConclusionsOur study provides the first direct evidence that DNMT3B-mediated CREG gene hypermethylation is a novel mechanism that contributes to endothelial dysfunction and atherosclerosis development. Blocking CREG methylation may represent a novel therapeutic approach to treat ox-LDL-induced atherosclerosis.
| S-EPMC7264464 | biostudies-literature
Project description:How parental histone (H3-H4)2 tetramers, the primary carriers of epigenetic modifications, are transferred onto leading and lagging strands of DNA replication forks for epigenetic inheritance remains elusive. Here we show that parental (H3-H4)2 tetramers are assembled into nucleosomes onto both leading and lagging strands, with a slight preference for lagging strands. The lagging-strand preference increases markedly in budding yeast cells lacking Dpb3 and Dpb4, two subunits of the leading strand DNA polymerase, Pol ε, owing to the impairment of parental (H3-H4)2 transfer to leading strands. Dpb3-Dpb4 binds H3-H4 in vitro and participates in the inheritance of heterochromatin. These results indicate that different proteins facilitate the transfer of parental (H3-H4)2 onto leading versus lagging strands and that Dbp3-Dpb4 plays an important role in this poorly understood process.
| S-EPMC6597248 | biostudies-literature
Project description:Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney-Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism of tumorigenesis in CT.
| S-EPMC4722532 | biostudies-literature
Project description:Except for regulatory CpG-island sequences, genomes of most mammalian cells are widely DNA-methylated. In oocytes though, DNAme is largely confined to transcribed regions. The mechanisms restricting de novo DNAme in oocytes and the relevance thereof for zygotic genome activation and embryonic development are largely unknown. Here we show that KDM2A and KDM2B, two histone demethylases, prevent genome-wide accumulation of histone H3 lysine 36 di-methylation, thereby impeding DNMT3A-catalyzed DNAme. We demonstrate that aberrant DNAme at CpG-islands inherited from Kdm2a/Kdm2b double mutant oocytes represses gene transcription in two-cell embryos. Aberrant maternal DNAme impairs pre-implantation embryonic development which is suppressed by Dnmt3a deficiency during oogenesis. Hence, KDM2A/KDM2B are essential for confining the oocyte methylome, thereby conferring competence for early embryonic development. Our research implies that the reprogramming capacity eminent to early embryos is insufficient for erasing aberrant DNAme from maternal chromatin, and that early development is vulnerable to gene dosage haplo-insufficiency effects.
2025-03-27 | GSE234968 | GEO
Project description:BACKGROUND: Protein-DNA interactions are essential for fundamental biological activities including DNA transcription, replication, packaging, repair and rearrangement. Proteins interacting with DNA can be classified into two categories of binding mechanisms - sequence-specific and non-specific binding. Protein-DNA specific binding provides a mechanism to recognize correct nucleotide base pairs for sequence-specific identification. Protein-DNA non-specific binding shows sequence independent interaction for accelerated targeting by interacting with DNA backbone. Both sequence-specific and non-specific binding residues contribute to their roles for interaction. RESULTS: The proposed framework has two stage predictors: DNA-binding residues prediction and binding mode prediction. In the first stage - DNA-binding residues prediction, the predictor for DNA specific binding residues achieves 96.45% accuracy with 50.14% sensitivity, 99.31% specificity, 81.70% precision, and 62.15% F-measure. The predictor for DNA non-specific binding residues achieves 89.14% accuracy with 53.06% sensitivity, 95.25% specificity, 65.47% precision, and 58.62% F-measure. While combining prediction results of sequence-specific and non-specific binding residues with OR operation, the predictor achieves 89.26% accuracy with 56.86% sensitivity, 95.63% specificity, 71.92% precision, and 63.51% F-measure. In the second stage, protein-DNA binding mode prediction achieves 75.83% accuracy while using support vector machine with multi-class prediction. CONCLUSION: This article presents the design of a sequence based predictor aiming to identify sequence-specific and non-specific binding residues in a transcription factor with DNA binding-mechanism concerned. The protein-DNA binding mode prediction was introduced to help improve DNA-binding residues prediction. In addition, the results of this study will help with the design of binding-mechanism concerned predictors for other families of proteins interacting with DNA.
| S-EPMC2788376 | biostudies-literature
Project description:DNA methylation (DNAme) controls gene expression, genome stability and cell identity in many mammalian organisms. Genomes of most somatic cells and spermatozoa are largely methylated, apart from CpG-dense sequences including gene promoters1. In mouse oocytes, DNAme is mostly limited to transcribed regions2,3. The mechanisms restricting global DNAme acquisition in developing oocytes and the relevance thereof for regulating gene expression and embryo development after fertilization are unknown. Here we show that the histone H3 lysine 36 dimethyl (H3K36me2) demethylases KDM2A and KDM2B redundantly execute multiple chromatin functions during oocyte development, which are vital to pre- and post-implantation development. Firstly, by serving as recruitment factors of variant Polycomb Repressive Complex 1 (vPRC1), they control genome-wide H2A mono-ubiquitination deposition (H2AK119u1) and PRC1-dependent gene repression4. Secondly, as demethylases, KDM2A/KDM2B prevent global H3K36me2 accumulation, thereby impeding DNMT3A-catalyzed de novo DNAme within PRC1-controlled promoter, genic, and intergenic regions, and even at non-PRC1-controlled CpG-dense gene promoters5. Decisively, we demonstrate that aberrant Dnmt3a-dependent DNAme established in Kdm2a/Kdm2b double mutant oocytes represses transcription from maternal loci in two-cell embryos and impairs pre-implantation development. Hence, KDM2A/KDM2B are essential for defining the appropriate oocyte DNA methylome which in turn conveys competence for early embryonic development. Our research implies that the reprogramming capacity eminent to early embryos is insufficient to erase aberrant DNAme from maternal chromatin. Lastly, our work shows that early development is vulnerable to gene dosage haplo-insufficiency effects, possibly in a parental-specific manner.
2025-03-27 | GSE234967 | GEO