Asher Mullard

No need for Klf4 and c-Myc when you reprogramme with Esrrb

Since the recent discovery that the transcription factors Oct4, Sox2, c-Myc and Klf4 can convert fibroblasts into induced pluripotent stem cells1, researchers have struggled to come to grips with the ins and outs of reprogramming. Now Huck-Hui Ng from the Genome Institute of Singapore and his colleagues have found that another reprogramming factor — Esrrb — can be used in place of Klf4 and c-Myc2. This discovery may help researchers better understand the basis of this process.

When the first reprogramming factors were identified, they were found from a screen of 24 embryonic stem cell–related transcription factors. Ng and his colleagues started by performing a similar screen on 18 previously untested transcription factors. "We screened for factors that can replace Klf4, and surprisingly we found Esrrb," says Ng. Further analysis revealed that a cocktail containing only Esrrb, Oct4 and Sox2 was enough to turn mouse embryonic fibroblasts into induced pluripotent stem cells.

"This is a very exciting and very important study," says Thomas Zwaka, who studies pluripotency at Baylor College of Medicine in Houston, Texas. Researchers have only found a handful of additional reprogramming factors, including Nanog, since the first four were identified. "The field is very Oct4- Sox2- and Nanog-centric," says Zwaka. Consequently, he welcomes any new work that expands the scope of the field. Once more reprogramming factors are identified, says Zwaka, researchers can then start to find areas of overlap, which will help to determine the molecular basis of reprogramming.

Although Esrrb — a nuclear receptor for which the ligand has not yet been identified — comes from a different family of transcription factors than Klf4, Ng already has one suspicion for why these two proteins can achieve the same effect. Previous studies have shown that Esrrb regulates Klf4 expression in embryonic stem cells, and Ng's study shows that Esrrb can act as a promoter of Klf4. "One possible mechanism for why Esrrb can replace Klf4 is perhaps because [it] can activate endogenous Klf4," says Ng.

Evidence also shows that Esrrb can bind other reprogramming factors, such as Nanog and Oct4. "This gives us a hint that maybe reprogramming needs factors that operate closely together," he says.


Source: Nature

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