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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Article first published online: 19 DEC 2012
Copyright © 2012 AlphaMed Press
Volume 31, Issue 1, pages 71–82, January 2013
How to Cite
Serrano, F., Calatayud, C. F., Blazquez, M., Torres, J., Castell, J. V. and Bort, R. (2013), Gata4 Blocks Somatic Cell Reprogramming By Directly Repressing Nanog. STEM CELLS, 31: 71–82. doi: 10.1002/stem.1272
Author contributions: F.S.: collection and/or assembly of data, data analysis and interpretation, and manuscript writing; C.F.C.: collection and/or assembly of data and data analysis and interpretation; M.B.: collection and/or assembly of data; J.T.: conception and design and manuscript writing; J.V.C.: financial support; R.B.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLS EXPRESS November 6, 2012.
- Issue published online: 19 DEC 2012
- Article first published online: 19 DEC 2012
- Accepted manuscript online: 6 NOV 2012 11:33PM EST
- Manuscript Accepted: 4 OCT 2012
- Manuscript Received: 2 MAY 2012
- Ministry of Science and Innovation. Grant Numbers: SAF2010-15376 2007–64414, SAF2011-29718
- Instituto de Salud Carlos III. Grant Number: PS09/00248
- CIBER de Enfermedades Hepaticas y Digestivas
- Instituto de Salud Carlos III, Spain
- Induced pluripotent stem cells;
- Nuclear reprogramming;
Somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells by ectopic expression of the four factors Oct4, Klf4, Sox2, and Myc. Here, we investigated the role of Gata4 in the reprogramming process and present evidence for a negative role of this family of transcription factors in the induction of pluripotency. Coexpression of Gata4 with Oct4, Klf4, and Sox2 with or without Myc in mouse embryonic fibroblasts greatly impaired reprogramming and endogenous Nanog expression. The lack of Nanog upregulation was associated with a blockade in the transition from the initiation phase of reprogramming to the full pluripotent state characteristic of iPS cells. Addition of Nanog to the reprogramming cocktail blocked the deleterious effects observed with Gata4 expression. Downregulation of endogenous Gata4 by short hairpin RNAs during reprogramming both accelerated and increased the efficiency of the process and augmented the mRNA levels of endogenous Nanog. Using comparative genomics, we identified a consensus binding site for Gata factors in an evolutionary conserved region located 9 kb upstream of the Nanog gene. Using chromatin immunoprecipitation, gel retardation, and luciferase assays, we found that Gata4 bound to this region and inhibited Nanog transcription in mouse embryonic stem cells. Overall, our results describe for first time the negative effect of Gata4 in the reprogramming of somatic cells and highlight the role of Gata factors in the transcriptional networks that control cell lineage choices in the early embryo. STEM Cells2013;31:71–82