Journal of Stem Cell Research & Therapy

Counteracting activities of OCT4 and KLF4 during reprogramming to pluripotency

3^rd International Conference and Exhibition on Cell & Gene Therapy

October 27-29, 2014 Embassy Suites Las Vegas, USA

Natalia Tapia, Ulf Tiemann, Adele G Marthaler, Kenjiro Adachi, Guangming Wu, Gerrit U L Fischedick, Marcos J Ara?zo-Bravo and Hans R Sch?ler

Accepted Abstracts: J Stem Cell Res Ther

Abstract:

Differentiated cells can be reprogrammed into induced pluripotent stem cells (iPSCs) after overexpressing four transcription factors, of which Oct4 is essential. To elucidate the role of Oct4 during reprogramming, we investigated the immediate transcriptional response to inducible Oct4 overexpression in various somatic murine cell types using micro array analysis. By downregulating somatic-specific genes, Oct4 induction influenced each transcriptional program in a unique manner. However, a significant upregulation of pluripotent markers could not be detected. Thus, OCT4 facilitates reprogramming by interfering with the somatic transcriptional network rather than by directly initiating a pluripotent gene expression program. Our results also show that the process of inducing de novo pluripotency does not simply consist of the activation of ESC-specific genes to the levels present in ESCs. Instead, some genes such as Mgarp need to be firstly downregulated and subsequently upregulated during the reprogramming process. We have elucidated the mechanism underlying this counterintuitive temporal expression pattern. In fact, KLF4 alone completely abolishes Mgarp expression while OCT4 alone induces high levels of Mgarp. This competitive interplay ensures that appropriate expression levels of Mgarp are maintained at different time points, which appear to be crucial for a successful reprogramming process, as either the permanent inhibition or the premature activation of Mgarp prevents the efficient generation of iPSCs. To our knowledge, Mgarp is the first gene described to date upon which KLF4 and OCT4 exhibit antagonistic effects. The mechanism that regulates the switch from KLF4- to OCT4-regulated Mgarp expression remains to be identified.

Biography :

Natalia Tapia after completing her PhD in Virology in the University of Barcelona, Spain, moved to the Max Planck Institute for Molecular Biomedicine, Germany where she started her research in the stem cell field. She is an independent junior group leader in the University of D?sseldorf, Germany since March 2014. She has published more than 20 papers in peer-reviewed journals..