The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells.

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.

[1]  R. Stewart,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[2]  Hidenori Akutsu,et al.  A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. , 2009, Cell stem cell.

[3]  Marcos J. Araúzo-Bravo,et al.  Direct reprogramming of human neural stem cells by OCT4 , 2009, Nature.

[4]  K. Hochedlinger,et al.  Tgfβ Signal Inhibition Cooperates in the Induction of iPSCs and Replaces Sox2 and cMyc , 2009, Current Biology.

[5]  Takashi Aoi,et al.  Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts , 2008, Nature Biotechnology.

[6]  Hans R. Schöler,et al.  New type of POU domain in germ line-specific protein Oct-4 , 1990, Nature.

[7]  R. Fletterick,et al.  Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1. , 2003, Molecular cell.

[8]  Thomas Lufkin,et al.  Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb , 2009, Nature Cell Biology.

[9]  Meng-Chun Hu,et al.  Liver receptor homolog‐1 localization in the nuclear body is regulated by sumoylation and cAMP signaling in rat granulosa cells , 2009, The FEBS journal.

[10]  Marius Wernig,et al.  c-Myc is dispensable for direct reprogramming of mouse fibroblasts. , 2008, Cell stem cell.

[11]  Huck-Hui Ng,et al.  Molecules that promote or enhance reprogramming of somatic cells to induced pluripotent stem cells. , 2009, Cell stem cell.

[12]  S. Kliewer,et al.  Orphan Nuclear Receptor LRH-1 Is Required To Maintain Oct4 Expression at the Epiblast Stage of Embryonic Development , 2005, Molecular and Cellular Biology.

[13]  J. Paré,et al.  The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element* , 2004, Journal of Biological Chemistry.

[14]  Janet Hager,et al.  Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity. , 2005, Journal of molecular biology.

[15]  N. D. Clarke,et al.  Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells , 2008, Cell.

[16]  H. Schöler,et al.  Formation of Pluripotent Stem Cells in the Mammalian Embryo Depends on the POU Transcription Factor Oct4 , 1998, Cell.

[17]  Shinya Yamanaka,et al.  Reprogramming somatic cells towards pluripotency by defined factors. , 2007, Current opinion in biotechnology.

[18]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[19]  Ge Guo,et al.  Nanog Is the Gateway to the Pluripotent Ground State , 2009, Cell.