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Nature DOI:10.1038/nature07056

Dissecting direct reprogramming through integrative genomic analysis.

Publication TypeJournal Article
Year of Publication2008
AuthorsMikkelsen, TS, Hanna, J, Zhang, X, Ku, M, Wernig, M, Schorderet, P, Bernstein, BE, Jaenisch, R, Lander, ES, Meissner, A
Date Published2008 Jul 03
KeywordsAnimals, Azacitidine, Cell Line, Cell Lineage, Cellular Reprogramming, Chromatin, DNA (Cytosine-5-)-Methyltransferase, DNA Methylation, Embryonic Stem Cells, Enzyme Inhibitors, Gene Expression Profiling, Gene Expression Regulation, Developmental, Genome, Genomics, Mice, Pluripotent Stem Cells, Transcription Factors

Somatic cells can be reprogrammed to a pluripotent state through the ectopic expression of defined transcription factors. Understanding the mechanism and kinetics of this transformation may shed light on the nature of developmental potency and suggest strategies with improved efficiency or safety. Here we report an integrative genomic analysis of reprogramming of mouse fibroblasts and B lymphocytes. Lineage-committed cells show a complex response to the ectopic expression involving induction of genes downstream of individual reprogramming factors. Fully reprogrammed cells show gene expression and epigenetic states that are highly similar to embryonic stem cells. In contrast, stable partially reprogrammed cell lines show reactivation of a distinctive subset of stem-cell-related genes, incomplete repression of lineage-specifying transcription factors, and DNA hypermethylation at pluripotency-related loci. These observations suggest that some cells may become trapped in partially reprogrammed states owing to incomplete repression of transcription factors, and that DNA de-methylation is an inefficient step in the transition to pluripotency. We demonstrate that RNA inhibition of transcription factors can facilitate reprogramming, and that treatment with DNA methyltransferase inhibitors can improve the overall efficiency of the reprogramming process.


Alternate JournalNature
PubMed ID18509334
PubMed Central IDPMC2754827
Grant ListU54 HG003067 / HG / NHGRI NIH HHS / United States
U54 HG003067-04 / HG / NHGRI NIH HHS / United States