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EMBRYONIC STEM CELLS/INDUCED PLURIPOTENT STEM CELLS

Enhanced Reprogramming of Xist by Induced Upregulation of Tsix and Dnmt3a

Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany

Key Words. Reprogramming • Cell fusion • Pluripotency • Oct4 • Xist • Histone deacetylase • Dnmt3a • Tsix

Correspondence: Correspondence: Hans R. Schöler, Ph.D., Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany. Telephone: 49-251-70365-300; Fax: 49-251-70365-399; e-mail: schoeler{at}mpi-muenster.mpg.de

Received on May 21, 2008; accepted for publication on August 21, 2008.

First published online in STEM CELLS EXPRESS  August 28, 2008.

Reactivation of Oct4 gene expression occurs within 2 days of fusion of somatic cells with pluripotent stem cells and within 9 days of postinfection of four transcription factors. We sought to determine whether somatic genome reprogramming is completed by the onset of Oct4 reactivation. The complex regulation of the reactivation of inactive X chromosome (Xi) serves as a model for studying reprogramming of chromatin domains. A time-course analysis of the DNA methylation, gene expression, and X inactivation-specific transcript (Xist)/Tsix RNA fluorescence in situ hybridization revealed that expression of pluripotency- and tissue-specific marker genes was reset to the level of pluripotent stem cells within 2 days of fusion, whereas reprogramming of Xist/reactivation of Xi took at least 9 days. We found that trichostatin A, which normally activates gene expression, results in downregulation of Xist. This is due to activation of Dnmt3a and Tsix, two negative regulators of Xist. Moreover, delayed reprogramming of Xist/reactivation of inactive X chromosome after cell fusion was accelerated by DNA methylation and histone deacetylation of Xist, which follow upregulation of Dnmt3a and Tsix.

Disclosure of potential conflicts of interest is found at the end of this article.