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

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Item Type:Article
Title:Molecular insights into reprogramming-initiation events mediated by the OSKM gene regulatory network
Creators Name:Mah, N. and Wang, Y. and Liao, M.C. and Prigione, A. and Jozefczuk, J. and Lichtner, B. and Wolfrum, K. and Haltmeier, M. and Floettmann, M. and Schaefer, M. and Hahn, A. and Mrowka, R. and Klipp, E. and Andrade-Navarro, M.A. and Adjaye, J.
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.
Keywords:Cell Aging, Epithelial-Mesenchymal Transition, Fibroblasts, Gene Expression Regulation, Gene Regulatory Networks, Kruppel-Like Transcription Factors, Biological Models, Nuclear Reprogramming, Octamer Transcription Factor-3, Pluripotent Stem Cells, Proto-Oncogene Proteins c-myc, Messenger RNA, Retroviridae, SOXB1 Transcription Factors, Time Factors, Transcriptome, Genetic Transduction, Transfection, Tumor Suppressor Protein p53, Animals
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e24351
Date:31 August 2011
Official Publication:https://doi.org/10.1371/journal.pone.0024351
PubMed:View item in PubMed

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