トウ　ヒデヒロ   藤　英博    所属   新潟薬科大学  応用生命科学部 学部付    職種   教授
言語種別	英語
発行・発表の年月	2023/08
形態種別	論文
査読	査読あり
標題	The DNMT3A ADD domain is required for efficient de novo DNA methylation and maternal imprinting in mouse oocytes
執筆形態	共著
掲載誌名	PLOS Genetics
掲載区分	国外
出版社・発行元	Public Library of Science (PLoS)
巻・号・頁	19(8),pp.e1010855
著者・共著者	Ryuji Uehara,Wan Kin Au Yeung,Keisuke Toriyama,Hiroaki Ohishi,Naoki Kubo,Hidehiro Toh,Isao Suetake,Kenjiro Shirane,Hiroyuki Sasaki
概要	Establishment of a proper DNA methylation landscape in mammalian oocytes is important for maternal imprinting and embryonic development. De novo DNA methylation in oocytes is mediated by the DNA methyltransferase DNMT3A, which has an ATRX-DNMT3-DNMT3L (ADD) domain that interacts with histone H3 tail unmethylated at lysine-4 (H3K4me0). The domain normally blocks the methyltransferase domain via intramolecular interaction and binding to histone H3K4me0 releases the autoinhibition. However, H3K4me0 is widespread in chromatin and the role of the ADD-histone interaction has not been studied in vivo. We herein show that amino-acid substitutions in the ADD domain of mouse DNMT3A cause dwarfism. Oocytes derived from homozygous females show mosaic loss of CG methylation and almost complete loss of non-CG methylation. Embryos derived from such oocytes die in mid-to-late gestation, with stochastic and often all-or-none-type CG-methylation loss at imprinting control regions and misexpression of the linked genes. The stochastic loss is a two-step process, with loss occurring in cleavage-stage embryos and regaining occurring after implantation. These results highlight an important role for the ADD domain in efficient, and likely processive, de novo CG methylation and pose a model for stochastic inheritance of epigenetic perturbations in germ cells to the next generation.
DOI	10.1371/journal.pgen.1010855
ISSN	1553-7404
PermalinkURL	https://dx.plos.org/10.1371/journal.pgen.1010855