title: The transcriptional and epigenomic foundations of ground state pluripotency.
abstract: Mouse embryonic stem (ES) cells grown in serum exhibit greater heterogeneity in morphology and expression of pluripotency factors than ES cells cultured in defined medium with inhibitors of two kinases (Mek and GSK3), a condition known as "2i" postulated to establish a naive ground state. We show that the transcriptome and epigenome profiles of serum- and 2i-grown ES cells are distinct. 2i-treated cells exhibit lower expression of lineage-affiliated genes, reduced prevalence at promoters of the repressive histone modification H3K27me3, and fewer bivalent domains, which are thought to mark genes poised for either up- or downregulation. Nonetheless, serum- and 2i-grown ES cells have similar differentiation potential. Precocious transcription of developmental genes in 2i is restrained by RNA polymerase II promoter-proximal pausing. These findings suggest that transcriptional potentiation and a permissive chromatin context characterize the ground state and that exit from it may not require a metastable intermediate or multilineage priming.
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Marks
authors.forename: Tüzer
authors.initials: T
authors.lastname: Kalkan
authors.forename: Roberta
authors.initials: R
authors.lastname: Menafra
authors.forename: Sergey
authors.initials: S
authors.lastname: Denissov
authors.forename: Kenneth
authors.initials: K
authors.lastname: Jones
authors.forename: Helmut
authors.initials: H
authors.lastname: Hofemeister
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nichols
authors.forename: Andrea
authors.initials: A
authors.lastname: Kranz
authors.forename: A Francis
authors.initials: AF
authors.lastname: Stewart
authors.forename: Austin
authors.initials: A
authors.lastname: Smith
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D044127:Epigenesis, Genetic; D016259:Genes, myc; D042421:Histone Code; D006657:Histones / Q000378:metabolism; D008745:Methylation; D051379:Mice; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D006657:Histones; D012319:RNA Polymerase II