The transcriptional and epigenomic foundations of ground state pluripotency

Hendrik Marks, Tüzer Kalkan, Roberta Menafra, Sergey Denissov, Kenneth Jones, Helmut Hofemeister, Jennifer Nichols, Andrea Kranz, A. Francis Stewart, Austin Smith, Hendrik G. Stunnenberg

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

665 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)590-604
Aantal pagina's15
TijdschriftCell
Volume149
Nummer van het tijdschrift3
DOI's
StatusGepubliceerd - 27 apr. 2012
Extern gepubliceerdJa

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