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

Abstract

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 Klf4. 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 iPSCs. 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.

Concise Review: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells: Close Enough or Yet Too Far Apart?

“…All of these aberrations likely appear because of the imperfection of the reprogramming procedure, as illustrated by the low efficiency of reprogramming. Efforts have to be made to improve culture conditions and factors [79] available to the cells during reprogramming, which could lower the number of stochastic steps the cell needs to breach in order to achieve pluripotency. This would likely increase the ratio of true versus bad quality iPSC colonies and lower the aberrations present in the cells.…”

Mechanism and methods to induce pluripotency

“…It is enriched in unfertilized eggs and zygotes, and could replace cMyc to produce iPSCs from adult cells with a higher efficiency and decreased tumorigenicity (Maekawa et al, 2011). Mechanistic studies revealed that the Glis1 protein interacts with Oct4, Sox2, and Klf4.…”

“…The gene targets of Glis1 include several Wnt ligands, Lin28a (a homologue of Lin28), Nanog, Mycn, Mycl1, and Foxa2. They propose that Glis1 facilitates iPSC formation by activating multiple pro-reprogramming pathways (Maekawa et al, 2011).…”

Overcoming barriers to the clinical utilization of iPSCs: reprogramming efficiency, safety and quality

“…Maekawa et al found that Glis1 markedly enhances the generation of iPSCs from both mouse and human fibroblasts when it is expressed together with OSK. Even more importantly, this four transcription factors generated mouse iPSCs can form germline-competent chimaeras (Maekawa et al, 2011). To undertake further research of the mechanism, they found Glis1 promotes multiple pro-reprogramming pathways, including Myc, Nanog, Lin28, Wnt, Essrb and the mesenchymal-epithelial transition, to promote the direct reprogramming of somatic cells during iPSC generation.…”

“…Tbx3 is necessary for safeguarding the pluripotency of mouse ES cells, as its knockdown elicits © Higher Education Press and Springer-Verlag Berlin Heidelberg 2012 differentiation (Ivanova et al, 2006). It appears to have pleiotrophic roles, as it is also required for mammary bud development and limb development (Carlson et al, 2002;Esteban et al, 2009;Graf et al, 2009;Maekawa et al, 2011). Furthermore, overexpression of Tbx3 in conjunction with Myc or oncogenic Ras leads to the efficient oncogenic transformation of mouse fibroblasts; it appears that Tbx3's role in oncogenic cooperation is to inhibit the induction of p53 and p19 ARF that is typically triggered by Myc and Ras (Carlson et al, 2002).…”