Scientists have discovered new clues to what makes embryonic stem (ES) cells tick. The findings may allow researchers to more easily unlock the therapeutic potential of the cells, which in theory can become any cell type in the body.
The key to tapping that potential is understanding the network of genes that keep ES cells forever young, as well as the triggers that allow them to differentiate into various tissues. No easy task. Scientists knew, for example, that all undifferentiated human ES cells express the genes OCT4, SOX2, and NANOG. But exactly what those genes do has been unclear.
Now, geneticist Richard Young of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues provide the most detailed look yet at what those three genes--and the proteins they code for--are doing inside the ES cell. Scientists suspected that the proteins were acting as transcription factors, turning some genes on while keeping others turned off by binding to regions of DNA called promoters. Young and his colleagues used a technique called genome-wide location analysis to study which promoters the three proteins attach to.
The gene trio seems to be a fairly close-knit team, often working together to control other genes. For example, the researchers found evidence that all three proteins camp out just upstream from the DNA that codes for OCT4, presumably keeping the gene turned on. In other cases, the proteins turn off the expression of other well-known genes involved in development of specific tissues. In all, the team found 623 genes affected by OCT4, 1271 genes that are apparently controlled by SOX2, and 1687 genes controlled by NANOG. A total of 353 genes appear to be controlled by all three, they report in a paper published online 8 September in Cell.
The dataset allows scientists to start to draw the "molecular circuitry" for the inner workings of ES cells, Young says. This might lead to better ways to control the notoriously fickle cells.
Indeed, such detailed molecular knowledge will be crucial before scientists can confidently use ES cell therapies in the clinic, says stem cell biologist Ari Brivanlou of Rockefeller University in New York. The work also takes scientists a step closer to being able to artificially activate the master switches, Young notes, which could lead to scientists finding a way to turn, say, skin cells directly into ES cells.