Dissecting direct reprogramming through integrative genomic analysis.

Nature
Authors
Keywords
Abstract

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.

Year of Publication
2008
Journal
Nature
Volume
454
Issue
7200
Pages
49-55
Date Published
2008 Jul 03
ISSN
1476-4687
URL
DOI
10.1038/nature07056
PubMed ID
18509334
PubMed Central ID
PMC2754827
Links
Grant list
U54 HG003067 / HG / NHGRI NIH HHS / United States
U54 HG003067-04 / HG / NHGRI NIH HHS / United States