Transcription regulation and chromatin structure in the pluripotent ground state

The use of mouse embryonic stem cells (ESCs) has provided invaluable insights into transcription and epigenetic regulation of pluripotency and self-renewal. Many of these insights were gained in mouse ESCs that are derived and maintained using serum, either on feeder cells or supplemented with the cytokine leukemia inhibitory factor (LIF). These 'serum' ESCs are in a metastable state characterized by the expression of many lineage-specifying genes. The use of two small-molecule kinase inhibitors (2i), targeting mitogen-activated protein kinase (MEK) and glycogen synthase kinase-3 (GSK3), has enabled derivation of mouse ESCs in defined serum-free conditions. These '2i' ESCs are more homogeneous in morphology and gene expression than serum ESCs, and are postulated to represent the ground state of pluripotency. Recent studies have shown that the epigenome and transcriptome of 2i and serum ESCs are markedly different, suggesting that these ESCs represent two distinct states of pluripotency regulated by different factors and pathways. There is growing evidence that the 2i ESCs closely parallel the early blastocyst cells of the inner cell mass (ICM) or even earlier stages, while serum cells possibly reflect later stages. In this review, we will focus on the difference in chromatin structure, transcription regulation and cell cycle regulation between ground state pluripotent 2i ESCs and serum ESCs, and compare to corresponding data in embryos if available. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development.