Generating iPS and out of Oct4? Worry not. Nr5a2 comes to the rescue!

The reprogramming field seems to be moving oh-so-fast.  First authorJian-Chien Dominic Heng (Genome Institute of Singapore) and colleagues in Singapore and Boston have discovered that a nuclear receptor known as Nr5a2 or Lrh-1 can replace Oct4, a critical transcription factor thought to be needed for generating induced pluripotent stem (iPS) cells.  This discovery adds another question to the current putative models to what molecular mechanisms are involved when a somatic cell is reprogrammed the the pluripotent state. It’s possible that Nr5a2, which has a multitude of biological functions,  has similar functions or binding sites as Oct4.  It’s also possible that Nr5a2 a direct target of Oct4 and has always been a critical factor in the reprogramming program. Nr5a2, who are you?

Here’s the abstract:

Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) with the introduction of Oct4, Sox2, Klf4, and c-Myc. Among these four factors, Oct4 is critical in inducing pluripotency because no transcription factor can substitute for Oct4, whereas Sox2, Klf4, and c-Myc can be replaced by other factors. Here we show that the orphan nuclear receptor Nr5a2 (also known as Lrh-1) can replace Oct4 in the derivation of iPSCs from mouse somatic cells, and it can also enhance reprogramming efficiency. Sumoylation mutants of Nr5a2 with enhanced transcriptional activity can further increase reprogramming efficiency. Genome-wide location analysis reveals that Nr5a2 shares many common gene targets with Sox2 and Klf4, which suggests that the transcription factor trio works in concert to mediate reprogramming. We also show that Nr5a2 works in part through activating Nanog. Together, we show that unrelated transcription factors can replace Oct4 and uncovers an exogenous Oct4-free reprogramming code.

Have access to Cell Stem Cell? Get the paper here.