Similar Datasets
Project description:The epithelial-to-mesenchymal transition (EMT) and metastasis of the cancer cells are closely associated with epigenetic changes of chromatin and reprogramming of transcriptomes. The DNA methyltransferases DNMT3A and DNMT3B possess DNA demethylation/dehydroxymethylation activities. Here, we show, by a range of molecular/cellular approaches, that active DNA demethylation activity of DNMT3A is required for hypoxia-induced EMT of the primary colon carcinoma SW480 cells, its genome-wide DNA demethylation, and promoter DNA demethylation/transcriptional activation of the EMT genes TWIST1 and SNAIL1. DNMT3A also positively regulates hypoxia-induced TWIST1 activation in other types of cancer cells. Mechanistic analysis supports a regulatory model, in which hypoxia-induced H3K36me3 mark recruits DNMT3A to demethylate CpG in the hypoxia-responsive element (HRE), thereby facilitating HIF-1α binding and TWIST1 activation. This study demonstrates for the first time an in vivo functional role of the active DNA demethylation activity of DNMT3A and its potential as a novel therapeutic target of anti-cancer development.
2025-08-13 | GSE251863 | GEO
Project description:The epithelial-to-mesenchymal transition (EMT) and metastasis of the cancer cells are closely associated with epigenetic changes of chromatin and reprogramming of transcriptomes. The DNA methyltransferases DNMT3A and DNMT3B possess DNA demethylation/dehydroxymethylation activities. Here, we show, by a range of molecular/cellular approaches, that active DNA demethylation activity of DNMT3A is required for hypoxia-induced EMT of the primary colon carcinoma SW480 cells, its genome-wide DNA demethylation, and promoter DNA demethylation/transcriptional activation of the EMT genes TWIST1 and SNAIL1. DNMT3A also positively regulates hypoxia-induced TWIST1 activation in other types of cancer cells. Mechanistic analysis supports a regulatory model, in which hypoxia-induced H3K36me3 mark recruits DNMT3A to demethylate CpG in the hypoxia-responsive element (HRE), thereby facilitating HIF-1α binding and TWIST1 activation. This study demonstrates for the first time an in vivo functional role of the active DNA demethylation activity of DNMT3A and its potential as a novel therapeutic target of anti-cancer development.
2025-08-13 | GSE252166 | GEO
Project description:H3K36me3-coupled DNA Demethylation by DNMT3A Is Essential for Hypoxia-Induced EMT of Cancer Cells
| PRJNA1057944 | ENA
Project description:H3K36me3-coupled DNA Demethylation by DNMT3A Is Essential for Hypoxia-Induced EMT of Cancer Cells [ChIP-Seq]
| PRJNA1057948 | ENA
Project description:H3K36me3-coupled DNA Demethylation by DNMT3A Is Essential for Hypoxia-Induced EMT of Cancer Cells [Bisulfite Sequencing]
| PRJNA1055568 | ENA
Project description:Establishment of the DNA methylation landscape of mammalian oocytes, mediated by the DNMT3A-DNMT3L complex, is crucial for reproduction and development. In mouse oocytes, high levels of DNA methylation occur exclusively in the transcriptionally active regions, with moderate to low levels of methylation in other regions. Histone H3K36me3 mediates the high levels of methylation in the transcribed regions; however, it is unknown which histone mark guides the methylation in the other regions. Here, we show that, in mouse oocytes, H3K36me2 is highly enriched in the X chromosome and is broadly distributed across all autosomes. Upon H3K36me2 depletion, DNA methylation in moderately methylated regions is selectively affected, and a methylation pattern unique to the X chromosome is switched to an autosome-like pattern. Furthermore, we find that simultaneous depletion of H3K36me2 and H3K36me3 results in global hypomethylation, comparable to that of DNMT3A depletion. Therefore, the two histone marks jointly provide the chromatin platform essential for guiding DNMT3A-dependent DNA methylation in mouse oocytes.
| S-EPMC9349174 | biostudies-literature
Project description:Histone modifications are integral to epigenetics through their influence on gene expression and cellular status. While it's established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2. Methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.
| S-EPMC10690240 | biostudies-literature
Project description:Recently, the structure of the DNMT3A2/3B3 heterotetramer complex bound to a mononucleosome was reported. Here, we investigate DNA methylation of recombinant unmodified, H3KC4me3 and H3KC36me3 containing mononucleosomes by DNMT3A2, DNMT3A catalytic domain (DNMT3AC) and the DNMT3AC/3B3C complex. We show strong protection of the nucleosomal bound DNA against methylation, but efficient linker-DNA methylation next to the nucleosome core. High and low methylation levels of two specific CpG sites next to the nucleosome core agree well with details of the DNMT3A2/3B3-nucleosome structure. Linker DNA methylation next to the nucleosome is increased in the absence of H3K4me3, likely caused by binding of the H3-tail to the ADD domain leading to relief of autoinhibition. Our data demonstrate a strong stimulatory effect of H3K36me3 on linker DNA methylation, which is independent of the DNMT3A-PWWP domain. This observation reveals a direct functional role of H3K36me3 on the stimulation of DNA methylation, which could be explained by hindering the interaction of the H3-tail and the linker DNA. We propose an evolutionary model in which the direct stimulatory effect of H3K36me3 on DNA methylation preceded its signaling function, which could explain the evolutionary origin of the widely distributed "active gene body-H3K36me3-DNA methylation" connection.
| S-EPMC8891314 | biostudies-literature
Project description:Excessive secretion of airway mucus and fluid accumulation are the common features of many respiratory diseases, which, in turn, induce cell hypoxia in the airway epithelium, resulting in epithelial-mesenchymal transition (EMT) and ultimately fibrosis. However, the mechanisms of EMT induced by hypoxia in the airway are currently unclear. To mimic the status of edematous fluid retention in the airway, we cultured primary mouse tracheal epithelial cells (MTECs) in a liquid-liquid interface (LLI) mode after full differentiation in a classic air-liquid interface (ALI) culture system. The cell hypoxia was verified by the physical characteristics and lactate production in cultured medium as well as HIF expression in MTECs cultured by LLI mode. EMT was evidenced and mainly mediated by basal cells, supported by flow cytometry and immunofluorescence assay. The differently expressed genes of basal and other airway epithelial cells were found to be enriched in the ribosome by our analysis of an MTEC single-cell RNA sequencing data set and Myc, the global regulator of ribosome biogenesis was identified to be highly expressed in basal cells. We next separated basal cells from bulk MTECs by flow cytometry, and the real-time PCR results showed that ribosome biogenesis was significantly upregulated in basal cells, whereas the inhibition of ribosome biogenesis alleviated the phosphorylation of the mammalian target of rapamycin/AKT and abrogated hypoxia-induced EMT in MTECs. Collectively, these observations strongly suggest that basal cells in the airway epithelium may mediate the process of hypoxia-induced EMT, partly through enhancing ribosome biogenesis.
| S-EPMC8696177 | biostudies-literature
Project description:Chronic hypoxia in the renal parenchyma is thought to induce epithelial-to-mesenchymal transition (EMT), leading to fibrogenesis and ultimately end-stage renal failure. Biliverdin reductase, recently identified as a serine/threonine/tyrosine kinase that may activate phosphatidylinositol 3-kinase (PI3K) and Akt, is upregulated in response to reactive oxygen species that may accompany hypoxia. We investigated this potential role of biliverdin reductase in hypoxia-induced renal tubular EMT. Expression of biliverdin reductase was upregulated in a human proximal tubule cell line (HK-2) cultured in hypoxic conditions (1% O2), and this was accompanied by reduced expression of E-cadherin and increased expression of the mesenchymal marker vimentin. Inhibiting PI3K reversed these changes, consistent with EMT. In normoxic conditions, overexpression of biliverdin reductase promoted similar characteristics of EMT, which were also reversed by inhibiting PI3K. Furthermore, using small interfering RNA (siRNA) to knockdown biliverdin reductase, we demonstrated that the enzyme associates with phosphorylated Akt and mediates the hypoxia-induced EMT phenotype. In vivo, expression of biliverdin reductase increased in the tubular epithelia of 5/6-nephrectomized rats, and immunohistochemistry of serial sections demonstrated similar localization of phosphorylated Akt and biliverdin reductase. In conclusion, biliverdin reductase mediates hypoxia-induced EMT through a PI3K/Akt-dependent pathway.
| S-EPMC2396754 | biostudies-literature