How embryonic stem cells maintain their identity

Two studies in the April 21, 2006 Cell report new details of the "genetic program" that affords embryonic stem cells the flexibility to give rise to any cell type in the body. Both groups identified mechanisms by which the embryonic stem cells of mice or humans keep from going down any one particular developmental path--that of muscle or nervous tissue, for example--while remaining "poised for activation."

Human embryonic stem cells can be kept in an undifferentiated state and selectively induced to form many specialized cell types, which could potentially replace cells lost or damaged by disease. The new findings may therefore aid in the realization of embryonic stem cells' therapeutic potential for regenerative medicine, according to the researchers, while furthering scientists' understanding of early development.

In one of the studies, Richard Young of the Whitehead Institute, and his colleagues, found that a member of the so-called Polycomb-group proteins is distributed across a special set of more than 200 developmental genes in human embryonic stem cells. Polycomb proteins are known to silence gene activity through chemical, or "epigenetic," modifications that alter the way that DNA is packaged into chromatin.

"We saw that the Polycomb protein preferred to occupy genes for most of the human developmental regulators to repress their activity," Young said. "These genes encode transcription factors that control development downstream of the embryo."

"This makes sense because were the developmental transcription factors 'on,' they would cause the embryonic stem cells to differentiate into specific cell types. It's an exciting result because it appears that the Polycomb proteins are generally responsible for maintaining developmental genes in an 'off' state."

Developmental genes found in association with the Polycomb protein were also occupied by histone proteins chemically modified at sites known to repress gene activity, they found. Histones--the chief proteins of chromatin--act as spools around which DNA winds and play a role in gene regulation.

Furthermore, they found, the silenced developmental genes became preferentially activated in human embryonic stem cells undergoing differentiation.

The findings help to explain earlier results in mice deficient for Polycomb proteins, Young said. The embryonic stem cells of those mice were "extremely unstable" and tended to specialize or die in culture, he said.

The results also add to the team's earlier finding, reported in Cell last year, that a trio of transcription factors--Oct4, Sox2, and nanog--are key regulators of embryonic stem cells' pluripotency and self-renewal," he said. Pluripotency refers to the cell's ability to develop into multiple cell types. The three factors apparently work together to activate pathways critical for stem cell identity, while repressing those leading to differentiation.

The researchers now report that the stem cell regulators Oct4, Sox2, and nanog co-occupy "a significant subset" of the developmental genes that are repressed by the Polycomb protein, further supporting a link between repression of developmental regulators and embryonic stem cell identity.

"This paper connects the two classes of embryonic stem cell regulators and provides a foundation for understanding the basic circuitry underlying human development," Young said.

In the second paper, Bradley Bernstein of Massachusetts General Hospital and Harvard Medical School, and his colleagues, report the discovery of a unique chromatin structure that marks key developmental genes in embryonic stem cells. The structure, which they call "bivalent domains," includes a pattern of chemical modification with both repressive and activating characteristics.

"In differentiated cells, chromatin is either 'on' or 'off' in accordance with the identity of that particular cell--rarely or never in between," Bernstein said.

"In embryonic stem cells, we found a totally different structure. The developmental genes of stem cells bear evidence of both active and repressive states. It's the first time this has been seen."

The genes appeared to be in a silent state, he explained, but with an activating influence that could allow them to turn on rapidly as needed. He suggested that by preserving the potential of key developmental genes, the bivalent domains may contribute to the unique ability of embryonic stem cells to form the many different tissues in the body.

When the researchers examined the state of the same genes in a collection of differentiated cell types, they found that the bivalent domains had been replaced by either repressive or activating modifications, in accordance with the cell's identity. Muscle cells, for example, must express the master genes for muscle, while silencing those specifically required for other cell types, Bernstein explained.

The team suggests that a comprehensive inventory of the presence or absence of bivalent domains over key developmental genes may provide valuable markers of cell identity and differentiation potential, in both health and disease. Bernstein said the findings also suggest that therapies that modify cells' epigenetic state might prove useful in the field of regenerative medicine.

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Bradley E. Bernstein of Massachusetts General Hospital in Charlestown, MA, Harvard Medical School in Boston, MA and the Broad Institute of Harvard and MIT in Cambridge, MA; Tarjei S. Mikkelsen of the Broad Institute of Harvard and MIT in Cambridge, MA and MIT in Cambridge, MA; Xiaohui Xie and Michael Kamal of the Broad Institute of Harvard and MIT in Cambridge, MA; Dana J. Huebert of Massachusetts General Hospital in Charlestown, MA; James Cuff and Ben Fry of the Broad Institute of Harvard and MIT in Cambridge, MA; Alex Meissner, Marius Wernig, Kathrin Plath and Rudolf Jaenisch of the Whitehead Institute for Biomedical Research, MIT in Cambridge, MA; Alexandre Wagschal and Robert Feil of the Institute of Molecular Genetics, CNRS UMR-5535 and University of Montpellier-II in Montpellier, France; Stuart L. Schreiber of the Broad Institute of Harvard and MIT in Cambridge, MA and Howard Hughes Medical Institute at the Department of Chemistry and Chemical Biology, Harvard University in Cambridge, MA; and Eric S. Lander of the Broad Institute of Harvard and MIT in Cambridge, MA and the Whitehead Institute for Biomedical Research, MIT in Cambridge, MA. This work was supported in part by grants from the National Cancer Institute (CA84198 to R.J.), the National Institute of Child Health and Human Development (HD045022 to R.J.), the National Institute for General Medical Sciences (GM38627 to S.L.S.), the National Human Genome Research Institute (to E.S.L.), and by funds from the Broad Institute of MIT and Harvard.

Bernstein et al.: "A bivalent chromatin structure marks key developmental genes in embryonic stem cells." Publishing in Cell 125, 315326, April 21, 2006 DOI 10.1016/j.cell.2006.02.041 www.cell.com

Tong Ihn Lee, Richard G. Jenner, Laurie A. Boyer, Matthew G. Guenther and Stuart S. Levine, Roshan M. Kumar, Brett Chevalier of the Whitehead Institute for Biomedical Research in Cambridge, MA; Sarah E. Johnstone and Megan F. Cole, of the Whitehead Institute for Biomedical Research in Cambridge, MA and the Massachusetts Institute of Technology in Cambridge, MA; Kyo-ichi Isono and Haruhiko Koseki, of the RIKEN Center for Allergy and Immunology in Yokohama Japan; Takuya Fuchikami and Kuniya Abe of the BioResource Center, RIKEN Tsukuba Institute in Tsukuba, Japan; Heather L. Murray of the Whitehead Institute for Biomedical Research in Cambridge, MA; Jacob P. Zucker of Howard Hughes Medical Institute, Harvard University in Cambridge,MA; Bingbing Yuan, George W. Bell, Elizabeth Herbolsheimer, Nancy M. Hannett, Kaiming Sun and Duncan T. Odom, of the Whitehead Institute for Biomedical Research in Cambridge, MA; Arie P. Otte of the University of Amsterdam in Amsterdam, The Netherlands; Thomas L. Volkert of the Whitehead Institute for Biomedical Research in Cambridge, MA; David P. Bartel of the Whitehead Institute for Biomedical Research in Cambridge, MA and the Massachusetts Institute of Technology in Cambridge, MA; Douglas A. Melton of Howard Hughes Medical Institute, Harvard University in Cambridge,MA; David K. Gifford of the Whitehead Institute for Biomedical Research in Cambridge, MA and MIT CSAIL, in Cambridge, MA; Rudolf Jaenisch and Richard A. Young of the Whitehead Institute for Biomedical Research in Cambridge, MA and the Massachusetts Institute of Technology in Cambridge, MA. This work was supported by NIH grants HG002668 and GM069400. T.L., T.L.V., D.K.G., and R.A.Y. consult for Agilent Technologies.

Lee et al.: "Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells." Publishing in Cell 125, 301313, April 21, 2006 DOI 10.1016/j.cell.2006.02.043 www.cell.com


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