The black box of pluripotency

What keeps stem cells pluripotent?

By | April 24, 2008

What keeps stem cells pluripotent? In the past six months researchers have linkurl:reprogrammed; human progenitor skin cells and linkurl:fully-differentiated; Beta cells back into a pluripotent state. Despite these advances, little is known so far about how pluripotency is regulated. To find out, researchers have set their sights on a group of mammalian regulator genes known as the Polycomb Complex, the uncharted territory of stem cell biology. This is the missing piece that will give researchers more control over their cell populations in developing stem cell-based linkurl:therapies.; In all cases of reprogramming, researchers treat cells with a cocktail of transcription factors that induce the cells back into a pluripotent state. These transcription factors make up a large subset of genes that are part of the Polycomb Complex. The Polycomb as a whole somehow "puts the brake on developmental regulators and at same time accelerates activity of genes important for self-renewal," linkurl:Konrad Hochedlinger,; stem cell biologist at Harvard Medical School, told The Scientist. The fruit fly equivalent of the Polycomb Complex is hinting at the mechanisms that regulate differentiation. "We are still looking at Drosophila, and then trying to carry this information over to the mammalian situation to ask, 'what do corresponding proteins do in regulating differentiation in mammalian cells?'" linkurl:Vincenzo Pirrotta,; stem cell researcher at Rutgers University, told The Scientist. In Drosophila, all Polycomb genes are counter-regulated by a group of proteins called the Trithorax complex. This protein complex has also been termed a Polycomb response element, and it is responsible for keeping the activity of the Polycomb Complex in check -- that is, repressing critical genes that signal differentiation. The Polycomb and Trithorax don't directly interact. The histone markers one imparts on DNA transcription indirectly repress the other. The two complexes "are acting one against the other," said Pirrotta. "The interaction depends on what one does and what the other one does, not necessarily [what happens] between the two of them." Some researchers have found that other protein complexes are responsible for recruiting the Polycomb and Trithorax complexes to the DNA binding sites that either trigger or repress differentiation in Drosophila. A recent linkurl:study; led by linkurl:Renato Paro,; at the Swiss Federal Institute of Technology (ETH) in Zurich, found that the Pleiohomeotic (Pho) repressor complex may be involved in recruiting the Polycomb complex in Drosophila, and repressing some genes that have already been induced. (Check out our May issue for a profile of ETH.) Are similar mechanisms at work in mammals? Genes associated with acute leukemias, called mixed lineage leukemia genes (MLL), are associated with genetic rearrangements, and some studies suggest that they may be Trithorax homologs. There are several MLL genes and proteins, each associated with a specific subset of genes. "From what is known so far it is MLL1 and MLL2 that are most likely to be like Drosophila Trithorax," said Pirrotta. Of course, mammals and fruit flies have different rates of development. Fruit flies have a more streamlined process of development, whereas mammalian complexity requires relatively slow development so that everything can find its correct place, therefore requiring more complex control mechanisms, Pirrotta pointed out. So far, Hochedlinger said, the molecular players involved in maintained pluripotency and differentiation remain elusive, and many questions remain unanswered. "The tools published in the past were critical to reveal where these [transcription] factors bind during the reprogramming process," he added. The next questions will be "what is the sequence of events; do Polycomb proteins bind first and then transcription factors, or is it the other way round? When does methylation occur? Now it's a black box."

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