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Versatility of stem cells controlled by alliances, competitions of proteins

Like people with a big choice to make, stem cells have a process to “decide” whether to transform into a specific cell type or to stay flexible, a state that biologists call “pluripotency.” Using a technology he invented, Brown researcher William Fairbrother and colleagues have discovered new molecular interactions in the process that will help regenerative medicine researchers better understand pluripotency.

In a paper published in advance online in the journal Genome Research, Fairbrother’s team showed that different proteins called transcription factors compete and cooperate in the cells to produce complex bindings along crucial sequences of DNA. This game of molecular “capture the flag,” played in teams and amid shifting alliances, appears to be a necessary part of what determines whether stem cells retain their pluripotency and whether specialized, or differentiated, cells can regain it.

In recent years scientists have reported spectacular successes in turning fully differentiated cells back into pluripotent stem cells, a process called reprogramming. But the animals derived from these cells often suffer higher rates of tumors and other problems, Fairbrother said. The reason may be because the complex details of the reprogramming process haven’t been fully understood. He said there are many misconceptions about how reprogramming transcription factors interact with DNA.

“Most people think of a protein binding to DNA as a single, surgical thing where you have this isolated binding event,” Fairbrother said. “But in fact we show that sometimes these binding events occur over hundreds of nucleotides so they seem more like great greasy globs of proteins that are forming. In addition, the proteins interact with each other, diversifying their function by appearing in complexes with with different partners at different places.”

“How do stem cells stay in the state where they can keep their options open?” Fairbrother said. “A key player is POU5F1. But what are the key players that could interact with it and modulate its function? We’ve developed technology to look at that question.”