title: Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution.
abstract: Ectopic expression of the four transcription factors Oct4, Sox2, c-Myc, and Klf4 is sufficient to confer a pluripotent state upon the fibroblast genome, generating induced pluripotent stem (iPS) cells. It remains unknown if nuclear reprogramming induced by these four factors globally resets epigenetic differences between differentiated and pluripotent cells. Here, using novel selection approaches, we have generated iPS cells from fibroblasts to characterize their epigenetic state. Female iPS cells showed reactivation of a somatically silenced X chromosome and underwent random X inactivation upon differentiation. Genome-wide analysis of two key histone modifications indicated that iPS cells are highly similar to ES cells. Consistent with these observations, iPS cells gave rise to viable high-degree chimeras with contribution to the germline. These data show that transcription factor-induced reprogramming leads to the global reversion of the somatic epigenome into an ES-like state. Our results provide a paradigm for studying the epigenetic modifications that accompany nuclear reprogramming and suggest that abnormal epigenetic reprogramming does not pose a problem for the potential therapeutic applications of iPS cells.
authors: Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Harvard Stem Cell Institute, 185 Cambridge Street, Boston, MA 02114, USA; Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
authors: Nimet
authors: N
authors: Maherali
authors: Department of Biological Chemistry, Johnson Comprehensive Cancer Center and Institute for Stem Cell Biology and Medicine, UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors: Rupa
authors: R
authors: Sridharan
authors: Department of Biological Chemistry, Johnson Comprehensive Cancer Center and Institute for Stem Cell Biology and Medicine, UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors: Wei
authors: W
authors: Xie
authors: Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Harvard Stem Cell Institute, 185 Cambridge Street, Boston, MA 02114, USA.
authors: Jochen
authors: J
authors: Utikal
authors: Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Harvard Stem Cell Institute, 185 Cambridge Street, Boston, MA 02114, USA.
authors: Sarah
authors: S
authors: Eminli
authors: Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Harvard Stem Cell Institute, 185 Cambridge Street, Boston, MA 02114, USA.
authors: Katrin
authors: K
authors: Arnold
authors: Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Harvard Stem Cell Institute, 185 Cambridge Street, Boston, MA 02114, USA.
authors: Matthias
authors: M
authors: Stadtfeld
authors: Department of Biological Chemistry, Johnson Comprehensive Cancer Center and Institute for Stem Cell Biology and Medicine, UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors: Robin
authors: R
authors: Yachechko
authors: Department of Biological Chemistry, Johnson Comprehensive Cancer Center and Institute for Stem Cell Biology and Medicine, UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors: Jason
authors: J
authors: Tchieu
authors: Whitehead Institute and Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors: Rudolf
authors: R
authors: Jaenisch
authors: Department of Biological Chemistry, Johnson Comprehensive Cancer Center and Institute for Stem Cell Biology and Medicine, UCLA School of Medicine, Los Angeles, CA 90095, USA; Molecular Biology Institute, Johnson Comprehensive Cancer Center and Institute for Stem Cell Biology and Medicine, UCLA School of Medicine, Los Angeles, CA 90095, USA. Electronic address: kplath@mednet.ucla.edu.
authors: Kathrin
authors: K
authors: Plath
authors: Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Harvard Stem Cell Institute, 185 Cambridge Street, Boston, MA 02114, USA. Electronic address: khochedlinger@helix.mgh.harvard.edu.
authors: Konrad
authors: K
authors: Hochedlinger
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005347:Fibroblasts / Q000166:cytology*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D036103:Nanotechnology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D049951:X Chromosome Inactivation
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors