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  Molecular insights into reprogramming-initiation events mediated by the OSKM gene regulatory network

Mah, N., Wang, Y., Liao, M. C., Prigione, A., Jozefczuk, J., Lichtner, B., et al. (2011). Molecular insights into reprogramming-initiation events mediated by the OSKM gene regulatory network. PLoS ONE, 6(8), e24351. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21909390 http://www.plosone.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0024351&representation=PDF.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-78CC-6 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-78CD-4
Genre: Journal Article

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 Creators:
Mah, N., Author
Wang, Y.1, Author              
Liao, M. C., Author
Prigione, A.1, Author              
Jozefczuk, J.1, Author              
Lichtner, B.1, Author              
Wolfrum, K.1, Author              
Haltmeier, M., Author
Flottmann, M., Author
Schaefer, M., Author
Hahn, A., Author
Mrowka, R., Author
Klipp, E.2, Author              
Andrade-Navarro, M. A., Author
Adjaye, J.1, Author              
Affiliations:
1Molecular Embryology and Aging (James Adjaye), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479654              
2Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433554              

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Free keywords: Animals; Cell Aging/genetics; Epithelial-Mesenchymal Transition/genetics; Fibroblasts/metabolism; Gene Expression Regulation; Gene Regulatory Networks/*genetics; Humans; Kruppel-Like Transcription Factors/*genetics/metabolism; Male; Mice; Models, Biological; Nuclear Reprogramming/*genetics; Octamer Transcription Factor-3/*genetics/metabolism; Pluripotent Stem Cells/metabolism; Proto-Oncogene Proteins c-myc/*genetics/metabolism; RNA, Messenger/genetics/metabolism; Retroviridae/genetics; SOXB1 Transcription Factors/*genetics/metabolism; Time Factors; Transcription, Genetic; Transcriptome; Transduction, Genetic; Transfection; Tumor Suppressor Protein p53/metabolism
 Abstract: Somatic cells can be reprogrammed to induced pluripotent stem cells by over-expression of OCT4, SOX2, KLF4 and c-MYC (OSKM). With the aim of unveiling the early mechanisms underlying the induction of pluripotency, we have analyzed transcriptional profiles at 24, 48 and 72 hours post-transduction of OSKM into human foreskin fibroblasts. Experiments confirmed that upon viral transduction, the immediate response is innate immunity, which induces free radical generation, oxidative DNA damage, p53 activation, senescence, and apoptosis, ultimately leading to a reduction in the reprogramming efficiency. Conversely, nucleofection of OSKM plasmids does not elicit the same cellular stress, suggesting viral response as an early reprogramming roadblock. Additional initiation events include the activation of surface markers associated with pluripotency and the suppression of epithelial-to-mesenchymal transition. Furthermore, reconstruction of an OSKM interaction network highlights intermediate path nodes as candidates for improvement intervention. Overall, the results suggest three strategies to improve reprogramming efficiency employing: 1) anti-inflammatory modulation of innate immune response, 2) pre-selection of cells expressing pluripotency-associated surface antigens, 3) activation of specific interaction paths that amplify the pluripotency signal.

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 Dates: 2011
 Publication Status: Published in print
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Title: PLoS ONE
Source Genre: Journal
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Pages: - Volume / Issue: 6 (8) Sequence Number: - Start / End Page: e24351 Identifier: ISSN: 1932-6203 (Electronic) 1932-6203 (Linking)