The Nuclear Receptor Nr5a2 Can Replace Oct4 in the Reprogramming of Murine Somatic Cells to Pluripotent Cells

• Published in: Cell stem cell 2010-02, Vol.6 (2), p.167-174
• Main Authors: Heng, Jian-Chien Dominic, Feng, Bo, Han, Jianyong, Jiang, Jianming, Kraus, Petra, Ng, Jia-Hui, Orlov, Yuriy L., Huss, Mikael, Yang, Lin, Lufkin, Thomas, Lim, Bing, Ng, Huck-Hui
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cells, Cultured; Cellular Reprogramming; Epigenesis, Genetic; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Genome-Wide Association Study; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Mice; Molecular and cellular biology; Mutation; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; Protein Binding; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; STEMCELL; Steroidogenic Factor 1 - genetics; Steroidogenic Factor 1 - metabolism; SUMO-1 Protein - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2009.12.009

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. [Display omitted] ► Nuclear receptor Nr5a2 enhances reprogramming of mouse fibroblasts ► Nr5a2 can replace Oct4 in the reprogramming cocktail ► Nr5a2 with enhanced transcriptional activity more effective in reprogramming ► DNA binding links Nr5a2 to the core pluripotency network