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First published online October 5, 2006
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2006-0383v1
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Submitted on June 23, 2006
Accepted on September 27, 2006

Embryonic Stem Cells

Epigenetic Mechanisms Contribute to Pluripotency and Cell Lineage Determination of Embryonic Stem Cells

Qiong Gan 1, Tadashi Yoshida 1, Oliver G. McDonald 1, Gary K. Owens 1*

1 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia

* To whom correspondence should be addressed. E-mail: gko{at}virginia.edu.


  Abstract

Epigenetic mechanisms, such as histone modifications and DNA methylation, have been shown to play a key role in the regulation of gene transcription. Results of recent studies indicate that a novel "bivalent" chromatin structure marks key developmental genes in embryonic stem (ES) cells wherein a number of untranscribed lineage-control genes, such as Sox1, Nkx2-2, Msx1, Irx3, and Pax3, are epigenetically modified with a unique combination of activating and repressive histone modifications that prime them for potential activation (or repression) upon cell lineage induction and differentiation. However, results of these studies also showed that a subset of lineage-control genes, such as Myf5 and Mash1, were not marked by these histone modifications, suggesting that distinct epigenetic mechanisms might exist for lineage-control genes in ES cells. In this review article, we will summarize evidence regarding possible mechanisms that control these unique histone modifications at lineage-control gene loci in ES cells and consider their possible contribution to ES cell pluripotency. In addition, we propose a novel "histone modification pulsing" model wherein individual pluripotent stem cells within the inner cell mass of blastocysts undergo transient asynchronous histone modifications at these developmental gene loci, thereby conferring differential responsiveness to environmental cues and morphogenic gradients important for cell lineage determination. Finally, we consider how these rapid histone modification exchanges become progressively more stable as ES cells undergo differentiation and maturation into specialized cell lineages.

Key Words. embryonic stem cells, pluripotency, epigenetics, histone modifications




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