In their study, the UW researchers focused on the function of two proteins: hypoxia-induced factor 1α and 2α, or HIF1α and HIF2α. These proteins are transcription factors which mean they affect the regulation of a number of genes, allowing them to dramatically alter a cell's behavior. The researchers showed through loss-of-function analysis that each protein, HIF1α as well as HIF2α is required for generation of stem cells through reprogramming.
To tease out the impact of HIF1α and 2α on cellular processes in more detail, they stabilized the proteins in an active form and tested what each protein could do alone. They found that when HIF1α was stabilized, the cells went into the glycolytic state and produced more induced pluripotent stem cells than normal.
However, when they just activated HIF2α, they found the cells failed to develop into stem cells. "This was a big surprise," said Mathieu. "These proteins are very similar but HIF1α gives you lots of stem cells; HIF2α, none."
If stabilized together, HIF2α won the battle, repressing all stem cell formation.
Further investigation found that HIF2α does indeed promote the shift to glycolysis in an early stage of the cells' reprogramming but if it persists too long has the opposite effect, blocking the progression to the stem cell state.
"HIF2α is like Darth Vader, originally a Jedi who falls to the dark side," said Ruohola-Baker. "While HIF1α, the good guy is beneficial for reprogramming throughout the process, HIF2α, if not eliminated, turns bad in the middle and represses pluripotency."
HIF2α does this in part by upregulating the pro
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