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Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

De novo establishment of DNA methylation is accomplished by DNMT3A and DNMT3B. Here, we analyze de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from DNA-hypomethylated 2i/L ES cells with genetic ablation of Dnmt3a or Dnmt3b. We identify 355 and 333 uniquely unmethylated gene...

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Autores principales: Yagi, Masaki, Kabata, Mio, Tanaka, Akito, Ukai, Tomoyo, Ohta, Sho, Nakabayashi, Kazuhiko, Shimizu, Masahito, Hata, Kenichiro, Meissner, Alexander, Yamamoto, Takuya, Yamada, Yasuhiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314859/
https://www.ncbi.nlm.nih.gov/pubmed/32581223
http://dx.doi.org/10.1038/s41467-020-16989-w
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author Yagi, Masaki
Kabata, Mio
Tanaka, Akito
Ukai, Tomoyo
Ohta, Sho
Nakabayashi, Kazuhiko
Shimizu, Masahito
Hata, Kenichiro
Meissner, Alexander
Yamamoto, Takuya
Yamada, Yasuhiro
author_facet Yagi, Masaki
Kabata, Mio
Tanaka, Akito
Ukai, Tomoyo
Ohta, Sho
Nakabayashi, Kazuhiko
Shimizu, Masahito
Hata, Kenichiro
Meissner, Alexander
Yamamoto, Takuya
Yamada, Yasuhiro
author_sort Yagi, Masaki
collection PubMed
description De novo establishment of DNA methylation is accomplished by DNMT3A and DNMT3B. Here, we analyze de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from DNA-hypomethylated 2i/L ES cells with genetic ablation of Dnmt3a or Dnmt3b. We identify 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b knockout (KO) 2i-MEFs, respectively. We find that Dnmt3a is exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes, while Dnmt3b has a dominant role on the X chromosome. Consistent with this, tissue-specific DNA methylation at PcG target genes is substantially reduced in Dnmt3a KO embryos. Finally, we find that human patients with DNMT3 mutations exhibit reduced DNA methylation at regions that are hypomethylated in Dnmt3 KO 2i-MEFs. In conclusion, here we report a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients.
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spelling pubmed-73148592020-06-26 Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development Yagi, Masaki Kabata, Mio Tanaka, Akito Ukai, Tomoyo Ohta, Sho Nakabayashi, Kazuhiko Shimizu, Masahito Hata, Kenichiro Meissner, Alexander Yamamoto, Takuya Yamada, Yasuhiro Nat Commun Article De novo establishment of DNA methylation is accomplished by DNMT3A and DNMT3B. Here, we analyze de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from DNA-hypomethylated 2i/L ES cells with genetic ablation of Dnmt3a or Dnmt3b. We identify 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b knockout (KO) 2i-MEFs, respectively. We find that Dnmt3a is exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes, while Dnmt3b has a dominant role on the X chromosome. Consistent with this, tissue-specific DNA methylation at PcG target genes is substantially reduced in Dnmt3a KO embryos. Finally, we find that human patients with DNMT3 mutations exhibit reduced DNA methylation at regions that are hypomethylated in Dnmt3 KO 2i-MEFs. In conclusion, here we report a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients. Nature Publishing Group UK 2020-06-24 /pmc/articles/PMC7314859/ /pubmed/32581223 http://dx.doi.org/10.1038/s41467-020-16989-w Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Yagi, Masaki
Kabata, Mio
Tanaka, Akito
Ukai, Tomoyo
Ohta, Sho
Nakabayashi, Kazuhiko
Shimizu, Masahito
Hata, Kenichiro
Meissner, Alexander
Yamamoto, Takuya
Yamada, Yasuhiro
Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development
title Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development
title_full Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development
title_fullStr Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development
title_full_unstemmed Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development
title_short Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development
title_sort identification of distinct loci for de novo dna methylation by dnmt3a and dnmt3b during mammalian development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314859/
https://www.ncbi.nlm.nih.gov/pubmed/32581223
http://dx.doi.org/10.1038/s41467-020-16989-w
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