title: A molecular roadmap of reprogramming somatic cells into iPS cells.
abstract: Factor-induced reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is inefficient, complicating mechanistic studies. Here, we examined defined intermediate cell populations poised to becoming iPSCs by genome-wide analyses. We show that induced pluripotency elicits two transcriptional waves, which are driven by c-Myc/Klf4 (first wave) and Oct4/Sox2/Klf4 (second wave). Cells that become refractory to reprogramming activate the first but fail to initiate the second transcriptional wave and can be rescued by elevated expression of all four factors. The establishment of bivalent domains occurs gradually after the first wave, whereas changes in DNA methylation take place after the second wave when cells acquire stable pluripotency. This integrative analysis allowed us to identify genes that act as roadblocks during reprogramming and surface markers that further enrich for cells prone to forming iPSCs. Collectively, our data offer new mechanistic insights into the nature and sequence of molecular events inherent to cellular reprogramming.
authors.affiliation: Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Polo
authors.forename: Endre
authors.initials: E
authors.lastname: Anderssen
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Walsh
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Schwarz
authors.forename: Christian M
authors.initials: CM
authors.lastname: Nefzger
authors.forename: Sue Mei
authors.initials: SM
authors.lastname: Lim
authors.forename: Marti
authors.initials: M
authors.lastname: Borkent
authors.forename: Effie
authors.initials: E
authors.lastname: Apostolou
authors.forename: Sara
authors.initials: S
authors.lastname: Alaei
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cloutier
authors.forename: Ori
authors.initials: O
authors.lastname: Bar-Nur
authors.forename: Sihem
authors.initials: S
authors.lastname: Cheloufi
authors.forename: Matthias
authors.initials: M
authors.lastname: Stadtfeld
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Figueroa
authors.forename: Daisy
authors.initials: D
authors.lastname: Robinton
authors.forename: Sridaran
authors.initials: S
authors.lastname: Natesan
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhu
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Konrad
authors.initials: K
authors.lastname: Hochedlinger
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D003584:Cytological Techniques / Q000379:methods*; D055106:Genome-Wide Association Study; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051379:Mice; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors