Molecular control of pluripotency
Introduction
Cells of the embryonic inner cell mass and their in vitro derivatives, embryonic stem (ES) cells, possess the remarkable property of pluripotency, the ability to give rise to all cells of the organism [1]. For this reason, ES cells are thought to hold great promise for regenerative medicine. Therefore, a detailed understanding of the mechanisms that enable propagation of ES cells in a pluripotent state, poised to execute a broad range of developmental programs, is essential to realizing their therapeutic potential. In metazoans, the establishment and maintenance of lineage-specific gene expression programs determines cell identity. Many regulators of these processes are highly conserved throughout evolution and are vital for development [2, 3]. External environmental factors can also influence gene regulation [4, 5, 6] but are not discussed in this review. Here, we focus on studies over the past two years that reveal how genetic and epigenetic factors control ES cell identity and influence the balance between pluripotency and differentiation in mammals.
Section snippets
Oct4, Sox2 and Nanog are key regulators of pluripotency
The homeodomain transcription factors Oct4 (also known as Pou5f1) and Nanog have been identified as crucial regulators of pluripotency and are predominantly expressed in pluripotent cell types (Table 1) (for detailed review, see [5]). Loss of Oct4 causes inappropriate differentiation of the inner cell mass and ES cells into trophectoderm, whereas overexpression of Oct4 results in differentiation into primitive endoderm and mesoderm, suggesting that precise Oct4 levels are necessary for
Transcriptional regulatory networks in pluripotent ES cells
Given that factors orchestrating early cell fate decisions also regulate ES cell pluripotency, Oct4, Sox2 and Nanog are thought to establish the initial genomic state from which all other gene expression patterns are derived during development. Recent genomics studies have enabled the construction of transcriptional regulatory networks in ES cells that provide a foundation for understanding how Oct4, Sox2 and Nanog control pluripotency and influence subsequent differentiation events. Two groups
Chromatin dynamics and epigenetic profile of pluripotent ES cells
Chromatin reorganization is essential for the establishment of new heritable gene expression programs that accompany lineage specification (Figure 2) [27]. For example, ES cell chromatin displays characteristics of transcriptionally permissive euchromatin, such as an abundance of acetylated histone modifications and increased accessibility to nucleases. Conversely, lineage specification is typified by a decrease in acetylation and concomitant increase in heterochromatin formation, indicating
Conclusions and prospects
The recent studies highlighted in this review have made important contributions toward elucidating the complexity of cell fate determination and suggest mechanisms for the stable propagation of a pluripotent state. Despite these efforts, Oct4 and Nanog remain the only two transcriptional regulators identified to date whose role is specific to pluripotent cells. Therefore, it will continue to be of interest how Oct4 and Nanog themselves are regulated and whether there are any other similar
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Tom DiCesare for help with illustrations, and members of the Jaenisch laboratory for critical review of the manuscript. This work was supported in part by grants from the National Institutes of Health and NCI to RJ.
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