Loss of the maintenance methyltransferase, xDnmt1, induces apoptosis in Xenopus embryos.
DNA methylation is necessary for normal embryogenesis in animals. Here we show that loss of the maintenance methyltransferase, xDnmt1p, triggers an apoptotic response during Xenopus development, which accounts for the loss of specific cell populations in hypomethylated embryos. Hypomethylation-induced apoptosis is accompanied by a stabilization in xp53 protein levels after the mid-blastula transition. Ectopic expression of HPV-E6, which promotes xp53 degradation, prevents cell death, implying that the apoptotic signal is mediated by xp53. In addition, inhibition of caspase activation by overexpression of Bcl-2 results in the development of cellular masses that resemble embryonic blastomas. Embryonic tissue explant experiments suggest that hypomethylation alters the developmental potential of early embryo cells and that apoptosis is triggered by differentiation. Our results imply that loss of DNA methylation in differentiated somatic cells provides a signal via p53 that activates cell death pathways.
Stancheva
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Genes and Development Group, The University of Edinburgh, Department of Biomedical Sciences, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
Hensey
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Meehan
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D000015:Abnormalities, Multiple; D000818:Animals; D017209:Apoptosis; D001755:Blastocyst / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D004475:Ectoderm / Q000637:transplantation; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000502:physiology* / Q000637:transplantation; D020287:In Situ Nick-End Labeling; D009373:Neoplasms, Germ Cell and Embryonal; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014981:Xenopus
D009856:Oncogene Proteins, Viral; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases