TY - JOUR
T1 - The transcriptional and epigenomic foundations of ground state pluripotency
AU - Marks, Hendrik
AU - Kalkan, Tüzer
AU - Menafra, Roberta
AU - Denissov, Sergey
AU - Jones, Kenneth
AU - Hofemeister, Helmut
AU - Nichols, Jennifer
AU - Kranz, Andrea
AU - Francis Stewart, A.
AU - Smith, Austin
AU - Stunnenberg, Hendrik G.
N1 - Funding Information:
We thank Eva Janssen-Megens, Anita Kaan, and Yan Tan for sequencing; Kees-Jan Françoijs, Hinri Kerstens, Simon van Heeringen, and Arjen Brinkman for bioinformatic assistance; and Rachel Walker for help with flow cytometry. We thank Paul Bertone for comments on the manuscript. Tatyana Nesterova and Neil Brockdorff provided the XT67E1 cells and Olga Ujhelly and Andras Dinnyes the HM1 cells. The pThr345-Ezh2 antibody was a gift from Danny Reinberg. The research leading to these results has received funding from the European Union grants HEROIC (18883; FP6/2005-2010), PluriSys (223485; FP7/2009), EuroSyStem (200720; FP7/2008), and ATLAS (221952; FP7/2009), the Deutsche Forschungsgemeinschaft SPP1356 Pluripotency and Reprogramming, and The Wellcome Trust. A.S. is a Medical Research Council Professor.
PY - 2012/4/27
Y1 - 2012/4/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84860351082&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.03.026
DO - 10.1016/j.cell.2012.03.026
M3 - Article
C2 - 22541430
AN - SCOPUS:84860351082
SN - 0092-8674
VL - 149
SP - 590
EP - 604
JO - Cell
JF - Cell
IS - 3
ER -