气候变化领域集成服务门户(CCPortal): Disabling de novo DNA methylation in embryonic stem cells allows an illegitimate fate trajectory

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DOI	10.1073/pnas.2109475118
	Disabling de novo DNA methylation in embryonic stem cells allows an illegitimate fate trajectory
	Kinoshita M.; Li M.A.; Barber M.; Mansfield W.; Dietmann S.; Smith A.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:38
英文摘要	Genome remethylation is essential for mammalian development but specific reasons are unclear. Here we examined embryonic stem (ES) cell fate in the absence of de novo DNA methyltransferases. We observed that ES cells deficient for both Dnmt3a and Dnmt3b are rapidly eliminated from chimeras. On further investigation we found that in vivo and in vitro the formative pluripotency transition is derailed toward production of trophoblast. This aberrant trajectory is associated with failure to suppress activation of Ascl2. Ascl2 encodes a bHLH transcription factor expressed in the placenta. Misexpression of Ascl2 in ES cells provokes transdifferentiation to trophoblast-like cells. Conversely, Ascl2 deletion rescues formative transition of Dnmt3a/b mutants and improves contribution to chimeric epiblast. Thus, de novo DNA methylation safeguards against ectopic activation of Ascl2. However, Dnmt3a/b-deficient cells remain defective in ongoing embryogenesis. We surmise that multiple developmental transitions may be secured by DNA methylation silencing potentially disruptive genes. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	DNA methylation; Embryonic stem cells; Pluripotency
语种	英语
scopus关键词	DNA methyltransferase 3A; DNA methyltransferase 3B; octamer transcription factor 4; octamer transcription factor 6; transcription factor Otx2; Article; Ascl2 gene; cell fate; cell lineage; cell transdifferentiation; chromatin; DNA methylation; ectoderm; embryo; embryo development; embryonic stem cell; gene; nonhuman; pluripotent stem cell; transcriptomics; trophoblast
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238797
作者单位	Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, CB2 0AW, United Kingdom; Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, United Kingdom; Living Systems Institute, University of Exeter, Exeter, EX4 4QD, United Kingdom; PetMedix Ltd, The Glenn Berger Building, Cambridge, CB22 3FH, United Kingdom; MRC Human Genetics Unit, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom; Institute for Informatics, Washington University School of Medicine in St. Louis, St. Louis, MO 63108-2212, United States
推荐引用方式 GB/T 7714	Kinoshita M.,Li M.A.,Barber M.,et al. Disabling de novo DNA methylation in embryonic stem cells allows an illegitimate fate trajectory[J],2021,118(38).
APA	Kinoshita M.,Li M.A.,Barber M.,Mansfield W.,Dietmann S.,&Smith A..(2021).Disabling de novo DNA methylation in embryonic stem cells allows an illegitimate fate trajectory.Proceedings of the National Academy of Sciences of the United States of America,118(38).
MLA	Kinoshita M.,et al."Disabling de novo DNA methylation in embryonic stem cells allows an illegitimate fate trajectory".Proceedings of the National Academy of Sciences of the United States of America 118.38(2021).