The Transcriptional and Epigenomic Foundations of Ground State Pluripotency

By H. Marks, Tüzer Kalkan, R. Menafra, S. Denissov, K. Jones, H. Hofemeister, Jennifer Nichols, A. Kranz, A. F. Stewart, Austin Smith and 1 more. Cell, 2012

858 citations recorded by the source corpus.

Summary 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c35f09bff4443d14f96ef69acb102091d8557396

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Citations in the corpus

Classification of low quality cells from single-cell RNA-seq data (2016, background): “These GO terms contain 56 key genes that are strongly involved in pluripotency such as Nanog, Klf4, Prdm14, and Tcl1, and have been previously observed to be differentially expressed between the two conditions [39].”
Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, neutral): “Mouse ESCs grown in the 2i condition appear to be a homogeneous population that has a transcriptome and histone modification profile distinct from that of serum-grown mouse ESCs (Marks et al., 2012).”
Metabolic Plasticity in Stem Cell Homeostasis and Differentiation (2012, neutral): “Moreover, kinase inhibitors (2i), which streamline germline-competent ESCderivation and prevent spontaneous differentiation, upregulate genes associated with metabolic functions (Marks et al., 2012).”
A double take on bivalent promoters. (2013, background): “Interestingly, these naı̈ve pluripotent ES cells display reduced levels of H3K27me3 at developmental promoters, and, consequently, fewer genes were classified as bivalent (Marks et al. 2012) because they fell below an arbitrary threshold previously used to identify H3K27me3 peaks.”
Systematic Identification of Culture Conditions for Induction and Maintenance of Naive Human Pluripotency (2014, positive): “Consistent with observations in naive pluripotent mouse ESCs (Marks et al., 2012), H3K27me3 was strongly reduced at the transcriptional start site (TSS) of Polycomb group target genes in naive human ESCs (Figures 7F and 7G).”