Development

The Fantastic Fourth No Longer

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Science  19 Feb 2010:
Vol. 327, Issue 5968, pp. 925
DOI: 10.1126/science.327.5968.925-a

The number of exogenously expressed factors that can reprogram somatic cells into what are called induced pluripotent stem cells (iPSCs) has grown over the past 3 years. The original quartet of transcription factors—Oct4, Sox2, Klf4, and c-Myc—heads a list that includes familial relatives of the last three and other proteins such as the transcription factor Nanog and the RNA-binding protein Lin28. Oct4 had appeared to be indispensable and thus had been considered an essential part of the reprogramming code.

However, Heng et al. report that Oct4 can be replaced. They screened 19 nuclear receptors and found that exogenous expression of the nuclear receptor Nr5a2 in mouse embryonic fibroblasts could enhance reprogramming efficiency by a factor of 4 as compared to the famous four factors alone. Moreover, Nr5a2 could in fact replace Oct4 and act with Sox2, Klf4, and c-Myc to reprogram somatic cells. The gene expression and chromatin modification profiles of these iPSCs (like the iPSCs generated by expression of the original four factors) were more similar to those of embryonic stem cells than those of mouse embryonic fibroblasts. Furthermore, the target genes of Nr5a2 overlap with targets of Sox2 and Klf4 that are important in embryonic stem cell identity, such as Nanog.

Cell Stem Cell 6, 167 (2010).

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