De novo DNA methylation drives 5hmC accumulation in mouse zygotes
| Autor: | Shoma Nakagawa, Zelpha D’Souza, Haruhiko Koseki, Manabu Nakayama, Hiroyuki Sasaki, Petra Hajkova, Nobuaki Kudo, Masashi Matsuda, Vesela Encheva, Rachel Amouroux, Kenjiro Shirane, Buhe Nashun, Aleksandra Turp, Elodie Ndjetehe, Peter W. S. Hill |
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| Jazyk: | angličtina |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
0301 basic medicine Zygote Fluorescent Antibody Technique Fertilization in Vitro Biology Immunofluorescence Mass Spectrometry DNA Methyltransferase 3A Dioxygenases Epigenesis Genetic Embryo Culture Techniques Hydroxylation Cytosine Mice 03 medical and health sciences chemistry.chemical_compound Proto-Oncogene Proteins medicine Animals DNA (Cytosine-5-)-Methyltransferases Mice Knockout medicine.diagnostic_test Gene Expression Regulation Developmental Embryo Cell Biology Methylation DNA Methylation Cellular Reprogramming Molecular biology Cell biology DNA-Binding Proteins Kinetics 030104 developmental biology DNA demethylation chemistry 5-Methylcytosine DNMT1 Reprogramming Biomarkers Chromatography Liquid |
| Zdroj: | Nature Cell Biology |
| ISSN: | 1476-4679 1465-7392 |
| DOI: | 10.1038/ncb3296 |
| Popis: | Zygotic epigenetic reprogramming entails genome-wide DNA demethylation that is accompanied by Tet methylcytosine dioxygenase 3 (Tet3)-driven oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC; refs 1-4). Here we demonstrate using detailed immunofluorescence analysis and ultrasensitive LC-MS-based quantitative measurements that the initial loss of paternal 5mC does not require 5hmC formation. Small-molecule inhibition of Tet3 activity, as well as genetic ablation, impedes 5hmC accumulation in zygotes without affecting the early loss of paternal 5mC. Instead, 5hmC accumulation is dependent on the activity of zygotic Dnmt3a and Dnmt1, documenting a role for Tet3-driven hydroxylation in targeting de novo methylation activities present in the early embryo. Our data thus provide further insights into the dynamics of zygotic reprogramming, revealing an intricate interplay between DNA demethylation, de novo methylation and Tet3-driven hydroxylation. |
| Databáze: | OpenAIRE |
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