TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling

doi:10.1038/nature20095

	TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling
	Dai, Hai-Qiang 1,2,3; Wang, Bang-An 1,2,3; Yang, Lu 4,5; Chen, Jia-Jia 1,2,3; Zhu, Guo-Chun 1,2,3; Sun, Mei-Ling6 ; Ge, Hao 4; Wang, Rui 4,5; Hapman, Deborah L. C.7; Tang, Fuchou 4,5; Sun, Xin 8,9; Xu, Guo-Liang1,2,3,6
	2016-10-27
发表期刊	NATURE (IF:50.5[JCR-2023],54.4[5-Year])
ISSN	0028-0836
卷号	538 期号:7626 页码:528-+
发表状态	已发表
DOI	10.1038/nature20095
摘要	Mammalian genomes undergo epigenetic modifications, including cytosine methylation by DNA methyltransferases (DNMTs). Oxidation of 5-methylcytosine by the Ten-eleven translocation (TET) family of dioxygenases can lead to demethylation(1-3). Although cytosine methylation has key roles in several processes such as genomic imprinting and X-chromosome inactivation, the functional significance of cytosine methylation and demethylation in mouse embryogenesis remains to be fully determined(4-9). Here we show that inactivation of all three Tet genes in mice leads to gastrulation phenotypes, including primitive streak patterning defects in association with impaired maturation of axial mesoderm and failed specification of paraxial mesoderm, mimicking phenotypes in embryos with gain-of-function Nodal signalling(10). Introduction of a single mutant allele of Nodal in the Tet mutant background partially restored patterning, suggesting that hyperactive Nodal signalling contributes to the gastrulation failure of Tet mutants. Increased Nodal signalling is probably due to diminished expression of the Lefty1 and Lefty2 genes, which encode inhibitors of Nodal signalling. Moreover, reduction in Lefty gene expression is linked to elevated DNA methylation, as both Lefty-Nodal signalling and normal morphogenesis are largely restored in Tet-deficient embryos when the Dnmt3a and Dnmt3b genes are disrupted. Additionally, a point mutation in Tet that specifically abolishes the dioxygenase activity causes similar morphological and molecular abnormalities as the null mutation. Taken together, our results show that TET-mediated oxidation of 5-methylcytosine modulates Lefty-Nodal signalling by promoting demethylation in opposition to methylation by DNMT3A and DNMT3B. These findings reveal a fundamental epigenetic mechanism featuring dynamic DNA methylation and demethylation crucial to regulation of key signalling pathways in early body plan formation.
收录类别	SCI
语种	英语
资助项目	'Key New Drug Creation and Manufacturing Program' of China[2014ZX09507002-005]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000386654400062
出版者	NATURE PUBLISHING GROUP
WOS关键词	ONE-STEP GENERATION ; METHYLTRANSFERASES DNMT3A ; CRE RECOMBINASE ; METHYLATION ; 5-METHYLCYTOSINE ; TRANSCRIPTOME ; EXPRESSION ; PROTEINS ; ROLES ; TDG
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1664
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_徐国良组生命科学与技术学院_硕士生
通讯作者	Sun, Xin; Xu, Guo-Liang
作者单位	1.Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol,State Key Lab Mol Biol, Shanghai 200031, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Inst Biochem & Cell Biol, Shanghai Key Lab Mol Androl, Shanghai 200031, Peoples R China 4.Peking Univ, Coll Life Sci, Biodynam Opt Imaging Ctr, Beijing 100871, Peoples R China 5.Peking Univ, Key Lab Cell Proliferat & Differentiat, Minist Educ, Beijing 100871, Peoples R China 6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China 7.Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA 8.Univ Wisconsin, Genet Lab, Madison, WI 53706 USA 9.Univ Calif San Diego, Dept Pediat, San Diego, CA 92093 USA
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Dai, Hai-Qiang,Wang, Bang-An,Yang, Lu,et al. TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling[J]. NATURE,2016,538(7626):528-+.
APA	Dai, Hai-Qiang.,Wang, Bang-An.,Yang, Lu.,Chen, Jia-Jia.,Zhu, Guo-Chun.,...&Xu, Guo-Liang.(2016).TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling.NATURE,538(7626),528-+.
MLA	Dai, Hai-Qiang,et al."TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling".NATURE 538.7626(2016):528-+.