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Gene-Suppressing Proteins Reveal Secrets of Stem Cells

Science  21 Apr 2006:
Vol. 312, Issue 5772, pp. 349a
DOI: 10.1126/science.312.5772.349a

Scientists have taken a step toward unlocking the mystery of “stemness”: that is, deciphering what makes embryonic stem (ES) cells able to replicate indefinitely and retain the potential to turn into any kind of body cell.

According to papers in Cell and Nature this week, key guardians of stemness are molecules called polycomb group proteins. A team from the Massachusetts Institute of Technology (MIT) and the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, reports that these proteins act in concert with others to repress most of the regulator genes whose proteins turn on key developmental genes. This keeps the ES cell in an undifferentiated state.

Who regulates the regulators?

A polycomb protein silences hundreds of genes that will direct the differentiation and development of ES cells when activated.

CREDIT: LEE ET AL., CELL 125, 1–13 (2006)

Polycomb group proteins are known to play a vital gene-suppressing role in the development of organisms as diverse as fruit flies and humans (Science, 29 April 2005, p. 624). Now, the researchers have tracked this role back to the very earliest stage of development. These proteins are “the founding ingredient for development,” says Rudolf Jaenisch, an author of both studies. “This is a major step forward in efforts to map the regulatory circuitry of embryonic stem cells, which constitutes the founding circuitry of human beings,” adds co-author Richard Young.

In the Cell study, the researchers surveyed all 3 billion base pairs in the human genome and identified every gene that a polycomb group protein, Suz12, binds to in ES cells. They started by treating ES cells so that Suz12 remained bound to its DNA targets even after the cells were broken open. They then dumped the cells' contents onto a chip containing DNA representing all of the human genome. The DNA sequences affixed to Suz12, which were labeled with a dye, bound to complementary sequences on the chip, revealing their identity. The scientists also report in Nature on a similar study with mouse ES cells using Suz12 and three other polycomb group proteins.

The two efforts identified hundreds of genes targeted by the polycomb group proteins. The vast majority of regulators primed to go into action later in development “are being occupied and repressed by polycomb,” says Young. Many of these silenced regulatory genes are also occupied by the ES cell transcription factors Oct4, Sox2, and Nanog. Both sets of proteins “cooperate in keeping a cell pluripotent and self-renewing,” says Jaenisch.

“These papers are really exciting because they point the way to one of the next levels of stem cell research,” says Princeton University stem cell scientist Ihor Lemischka. The new, fuller picture of polycomb group proteins, adds Young, may help scientists guide ES cell gene expression and push cell populations to develop into desired types, such as neurons or insulin-making pancreatic cells.

The same issue of Cell also features a report from the laboratory of Eric Lander at the Broad Institute of Harvard and MIT that highlights the importance of chromatin, the protein package surrounding DNA, in keeping mouse ES cells pluripotent. The scientists, led by Bradley E. Bernstein, found certain chromatin motifs near genes important for development that can repress the genes while at the same time keeping them poised for activation. These chromatin features, which they labeled “bivalent domains,” exert control over many of the same regulatory genes targeted by polycomb proteins.

The three papers “provide a wealth of detailed information” on what keeps ES cells pluripotent, says Vincenzo Pirrotta, a molecular biologist at Rutgers University in Piscataway, New Jersey. The polycomb papers demonstrate that those proteins and ES cell transcription factors bind to “a largely common set of genes.” The Bernstein paper then addresses how genes silenced by these factors ultimately become activated. Together, says Pirrotta, the papers have “defined the important players and the sites of action” that must be studied to get to the root of what it is to be a stem cell.

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