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STEM CELL GENOMICS AND PROTEOMICS

Pluripotency Associated Genes Are Reactivated by Chromatin-Modifying Agents in Neurosphere Cells

^aInstitute for Biomedical Engineering, Department of Cell Biology, and
^bHelmholtz Institute for Biomedical Engineering, Rheinisch-Westfälische Technische Hochscule Aachen University, Aachen, Germany;
^cInstitute for Medical Radiation and Cell Research, University of Würzburg, Würzburg, Germany;
^dIn Vitro Differentiation Group, Institute of Plant Genetics and Crop Plant Research, Gatersleben, Germany

Key Words. Neurosphere cells • Epigenetics • Reprogramming • Hematopoiesis • 5-Azacytidine • Trichostatin A • Embryonic stem cells • Pluripotency

Correspondence: Martin Zenke, Ph.D., Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Pauwelsstrasse 30, 52074 Aachen, Germany. Telephone: 49-241-80-80760; Fax: 49-241-80-82008; e-mail: martin.zenke{at}rwth-aachen.de

Received August 7, 2007; accepted for publication January 9, 2008.
First published online in STEM CELLS EXPRESS   January 17, 2008.



Chromatin architecture in stem cells determines the pattern of gene expression and thereby cell identity and fate. The chromatin-modifying agents trichostatin A (TSA) and 5-Aza-2'-deoxycytidine (AzaC) affect histone acetylation and DNA methylation, respectively, and thereby influence chromatin structure and gene expression. In our previous work, we demonstrated that TSA/AzaC treatment of neurosphere cells induces hematopoietic activity in vivo that is long-term, multilineage, and transplantable. Here, we have analyzed the TSA/AzaC-induced changes in gene expression by global gene expression profiling. TSA/AzaC caused both up- and downregulation of genes, without increasing the total number of expressed genes. Chromosome analysis showed no hot spot of TSA/AzaC impact on a particular chromosome or chromosomal region. Hierarchical cluster analysis revealed common gene expression patterns among neurosphere cells treated with TSA/AzaC, embryonic stem (ES) cells, and hematopoietic stem cells. Furthermore, our analysis identified several stem cell genes and pluripotency-associated genes that are induced by TSA/AzaC in neurosphere cells, including Cd34, Cd133, Oct4, Nanog, Klf4, Bex1, and the Dppa family members Dppa2, 3, 4, and 5. Sox2 and c-Myc are constitutively expressed in neurosphere cells. We propose a model in which TSA/AzaC, by removal of epigenetic inhibition, induces the reactivation of several stem cell and pluripotency-associated genes, and their coordinate expression enlarges the differentiation potential of somatic precursor cells.

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