Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1

Reprogramming of differentiated somatic cells to induced pluripotent stem (iPS) cells by exogenous expression of key transcription factors (Oct4, Sox2, Klf4 and c-Myc) has potential therapeutic applications. c-Myc enhances the efficiency of reprogramming, but the safety of using this oncogene has long been a concern. Now, Shinya Yamanaka and colleagues have found that the transcription factor Glis1 effectively and specifically promotes reprogramming of human and mouse somatic cells to iPS cells. Glis1 is highly enriched in unfertilized eggs and one-cell-stage embryos, and might be a link between reprogramming during iPS cell generation and after nuclear transfer into zygotes. Induced pluripotent stem cells (iPSCs) are generated from somatic cells by the transgenic expression of three transcription factors collectively called OSK: Oct3/4 (also called Pou5f1), Sox2 and Klf41. However, the conversion to iPSCs is inefficient. The proto-oncogene Myc enhances the efficiency of iPSC generation by OSK but it also increases the tumorigenicity of the resulting iPSCs2. Here we show that the Gli-like transcription factor Glis1 (Glis family zinc finger 1) markedly enhances the generation of iPSCs from both mouse and human fibroblasts when it is expressed together with OSK. Mouse iPSCs generated using this combination of transcription factors can form germline-competent chimaeras. Glis1 is enriched in unfertilized oocytes and in embryos at the one-cell stage. DNA microarray analyses show that Glis1 promotes multiple pro-reprogramming pathways, including Myc, Nanog, Lin28, Wnt, Essrb and the mesenchymal–epithelial transition. These results therefore show that Glis1 effectively promotes the direct reprogramming of somatic cells during iPSC generation.