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Originally published as MBC in Press, 10.1091/mbc.E05-06-0572 on September 29, 2005

Vol. 16, Issue 12, 5719-5735, December 2005

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Induction of Dedifferentiation, Genomewide Transcriptional Programming, and Epigenetic Reprogramming by Extracts of Carcinoma and Embryonic Stem Cells{boxd}

Christel K. Taranger, Agate Noer, Anita L. Sørensen, Anne-Mari Håkelien, Andrew C. Boquest, and Philippe Collas

Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway

Submitted June 28, 2005; Revised September 15, 2005; Accepted September 16, 2005
Monitoring Editor: Carl-Henrik Heldin

Functional reprogramming of a differentiated cell toward pluripotency may have long-term applications in regenerative medicine. We report the induction of dedifferentiation, associated with genomewide programming of gene expression and epigenetic reprogramming of an embryonic gene, in epithelial 293T cells treated with an extract of undifferentiated human NCCIT carcinoma cells. 293T cells exposed for 1 h to extract of NCCIT cells, but not of 293T or Jurkat T-cells, form defined colonies that are maintained for at least 23 passages in culture. Microarray and quantitative analyses of gene expression reveal that the transition from a 293T to a pluripotent cell phenotype involves a dynamic up-regulation of hundreds of NCCIT genes, concomitant with down-regulation of 293T genes and of indicators of differentiation such as A-type lamins. Up-regulated genes encompass embryonic and stem cell markers, including OCT4, SOX2, NANOG, and Oct4-responsive genes. OCT4 activation is associated with DNA demethylation in the OCT4 promoter and nuclear targeting of Oct4 protein. In fibroblasts exposed to extract of mouse embryonic stem cells, Oct4 activation is biphasic and RNA-PolII dependent, with the first transient rise of Oct4 up-regulation being necessary for the second, long-term activation of Oct4. Genes characteristic of multilineage differentiation potential are also up-regulated in NCCIT extract-treated cells, suggesting the establishment of "multilineage priming." Retinoic acid triggers Oct4 down-regulation, de novo activation of A-type lamins, and nestin. Furthermore, the cells can be induced to differentiate toward neurogenic, adipogenic, osteogenic, and endothelial lineages. The data provide a proof-of-concept that an extract of undifferentiated carcinoma cells can elicit differentiation plasticity in an otherwise more developmentally restricted cell type.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E05-06-0572) on September 29, 2005.

Abbreviations used: CHX, cycloheximide; DRB, 5,6-dichloro-1-D-ribofuranosyl benzimidazole; ECC, embryonal carcinoma cell; EGC, embryonal germ cell; EGFP, enhanced green fluorescent protein; ESC, embryonic stem cell; FCS, fetal calf serum; HBSS, Hank's balanced salt solution; LIF, leukemia inhibitory factor; NTP, nucleotide triphosphate; PBS, phosphate-buffered saline; SLO, streptolysin O.

{boxd} The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Philippe Collas (philippe.collas{at}medisin.uio.no).




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