title: Naive pluripotency is associated with global DNA hypomethylation.
abstract: Naive pluripotent embryonic stem cells (ESCs) and embryonic germ cells (EGCs) are derived from the preimplantation epiblast and primordial germ cells (PGCs), respectively. We investigated whether differences exist between ESCs and EGCs, in view of their distinct developmental origins. PGCs are programmed to undergo global DNA demethylation; however, we find that EGCs and ESCs exhibit equivalent global DNA methylation levels. Inhibition of MEK and Gsk3b by 2i conditions leads to pronounced reduction in DNA methylation in both cell types. This is driven by Prdm14 and is associated with downregulation of Dnmt3a and Dnmt3b. However, genomic imprints are maintained in 2i, and we report derivation of EGCs with intact genomic imprints. Collectively, our findings establish that culture in 2i instills a naive pluripotent state with a distinctive epigenetic configuration that parallels molecular features observed in both the preimplantation epiblast and nascent PGCs.
authors: Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors: Harry G
authors: HG
authors: Leitch
authors: Kirsten R
authors: KR
authors: McEwen
authors: Aleksandra
authors: A
authors: Turp
authors: Vesela
authors: V
authors: Encheva
authors: Tom
authors: T
authors: Carroll
authors: Nils
authors: N
authors: Grabole
authors: William
authors: W
authors: Mansfield
authors: Buhe
authors: B
authors: Nashun
authors: Jaysen G
authors: JG
authors: Knezovich
authors: Austin
authors: A
authors: Smith
authors: M Azim
authors: MA
authors: Surani
authors: Petra
authors: P
authors: Hajkova
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D018392:Genomic Imprinting; D005854:Germ Cells / Q000166:cytology* / Q000502:physiology; D005855:Germ Layers / Q000166:cytology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D000097584:DNA Methyltransferase 3B
chemical_list: D001549:Benzamides; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins; D004159:Diphenylamine; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D020930:MAP Kinase Kinase Kinases; D011725:Pyridines; D011743:Pyrimidines; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D000097584:DNA Methyltransferase 3B; C473711:Chir 99021; C000715535:Dnmt3a protein, mouse; C531066:Prdm14 protein, mouse; C506614:mirdametinib; C000605507:Gsk3b protein, mouse