دورية أكاديمية
Distinct and stage-specific contributions of TET1 and TET2 to stepwise cytosine oxidation in the transition from naive to primed pluripotency.
| العنوان: | Distinct and stage-specific contributions of TET1 and TET2 to stepwise cytosine oxidation in the transition from naive to primed pluripotency. |
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| المؤلفون: | Mulholland CB; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany., Traube FR; Department of Chemistry and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Munich, Germany., Ugur E; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany., Parsa E; Department of Chemistry and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Munich, Germany., Eckl EM; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany., Schönung M; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany., Modic M; Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, London, UK., Bartoschek MD; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany., Stolz P; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany., Ryan J; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany., Carell T; Department of Chemistry and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Munich, Germany., Leonhardt H; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany. h.leonhardt@lmu.de., Bultmann S; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany. bultmann@bio.lmu.de. |
| المصدر: | Scientific reports [Sci Rep] 2020 Jul 21; Vol. 10 (1), pp. 12066. Date of Electronic Publication: 2020 Jul 21. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: London : Nature Publishing Group, copyright 2011- |
| مواضيع طبية MeSH: | Cell Differentiation* , Oxidation-Reduction*, Cytosine/*metabolism , DNA-Binding Proteins/*genetics , Embryonic Stem Cells/*cytology , Embryonic Stem Cells/*metabolism , Proto-Oncogene Proteins/*genetics, Animals ; CRISPR-Cas Systems ; Chromatography, High Pressure Liquid ; DNA Methylation ; DNA-Binding Proteins/metabolism ; Dioxygenases ; Epigenesis, Genetic ; Mice ; Mice, Knockout ; Proteome ; Proteomics ; Proto-Oncogene Proteins/metabolism ; Tandem Mass Spectrometry |
| مستخلص: | Cytosine DNA bases can be methylated by DNA methyltransferases and subsequently oxidized by TET proteins. The resulting 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) are considered demethylation intermediates as well as stable epigenetic marks. To dissect the contributions of these cytosine modifying enzymes, we generated combinations of Tet knockout (KO) embryonic stem cells (ESCs) and systematically measured protein and DNA modification levels at the transition from naive to primed pluripotency. Whereas the increase of genomic 5-methylcytosine (5mC) levels during exit from pluripotency correlated with an upregulation of the de novo DNA methyltransferases DNMT3A and DNMT3B, the subsequent oxidation steps turned out to be far more complex. The strong increase of oxidized cytosine bases (5hmC, 5fC, and 5caC) was accompanied by a drop in TET2 levels, yet the analysis of KO cells suggested that TET2 is responsible for most 5fC formation. The comparison of modified cytosine and enzyme levels in Tet KO cells revealed distinct and differentiation-dependent contributions of TET1 and TET2 to 5hmC and 5fC formation arguing against a processive mechanism of 5mC oxidation. The apparent independent steps of 5hmC and 5fC formation suggest yet to be identified mechanisms regulating TET activity that may constitute another layer of epigenetic regulation. |
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| المشرفين على المادة: | 0 (DNA-Binding Proteins) 0 (Proteome) 0 (Proto-Oncogene Proteins) 0 (TET1 protein, mouse) 8J337D1HZY (Cytosine) EC 1.13.11.- (Dioxygenases) EC 1.13.11.- (Tet2 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20200723 Date Completed: 20201221 Latest Revision: 20211204 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC7374584 |
| DOI: | 10.1038/s41598-020-68600-3 |
| PMID: | 32694513 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2045-2322 |
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| DOI: | 10.1038/s41598-020-68600-3 |