Epigenetic control of embryonic stem cell fate

Embryonic stem (ES) cells have the ability to self-renew, producing daughter cells with equivalent developmental potential, or to differentiate into more specialized cells. ES cells are derived from the inner cell mass of the preimplantation embryo and are pluripotent, as they are able to differentiate into cells of the three germ layers, both in vitro and in vivo (Evans and Kaufman, 1981; Thomson et al., 1998). Three transcription factors, OCT4, SOX2, and NANOG, cooperate to ensure the self-renewal and pluripotency of ES cells (Boyer et al., 2005; Loh et al., 2006). These factors are highly expressed in undifferentiated ES cells and physically interact with each other in large protein complexes (Wang et al., 2006; van den Berg et al., 2010). OCT4, SOX2, and NANOG are transcriptionally interconnected and co-occupy promoters of actively transcribed genes that promote ES cell self-renewal such as KLF4 (Boyer et al., 2005; Loh et al., 2006; Kim et al., 2008). They also occupy genes encoding a large set of developmental regulators that are silent in ES cells, but whose expression is associated with lineage commitment and cellular differentiation (Fig. 1; Boyer et al., 2005; Loh et al., 2006). The fact that the three key regulators can activate some genes and repress others is thought to be caused by the chromatin packaging in ES cells that are regulated by epigenetic factors. Epigenetics refers to heritable changes in gene expression that are independent of nucleotide sequence. This is achieved by regulating gene activity through alterations of chromatin structure, such as posttranslational modifications of the histones and DNA methylation, which can be either permissive or restrictive for transcription. These changes are catalyzed by histone and DNA modification enzymes that work in coordination to coregulate the balance between pluripotency and lineagespecific differentiation. The question is how these multiple regulatory mechanisms are coordinated to control the transcriptional state of pluripotent versus developmental genes in ES cells and during in vitro differentiation of ES cells. In this Review, we describe recent advances in the understanding of the role of the repressive epigenetic marks deposited by Polycomb group (PcG) repressive complexes and DNA methyl transferases (DNMTs) on ES cell self-renewal and differentiation.