title: The epithelial-mesenchymal transition factor SNAIL paradoxically enhances reprogramming.
abstract: Reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs) entails a mesenchymal to epithelial transition (MET). While attempting to dissect the mechanism of MET during reprogramming, we observed that knockdown (KD) of the epithelial-to-mesenchymal transition (EMT) factor SNAI1 (SNAIL) paradoxically reduced, while overexpression enhanced, reprogramming efficiency in human cells and in mouse cells, depending on strain. We observed nuclear localization of SNAI1 at an early stage of fibroblast reprogramming and using mouse fibroblasts expressing a knockin SNAI1-YFP reporter found cells expressing SNAI1 reprogrammed at higher efficiency. We further demonstrated that SNAI1 binds the let-7 promoter, which may play a role in reduced expression of let-7 microRNAs, enforced expression of which, early in the reprogramming process, compromises efficiency. Our data reveal an unexpected role for the EMT factor SNAI1 in reprogramming somatic cells to pluripotency.
authors.affiliation: Division of Pediatric Hematology/Oncology, Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: junternaehrer@llu.edu.
authors.forename: Juli J
authors.initials: JJ
authors.lastname: Unternaehrer
authors.affiliation: Division of Pediatric Hematology/Oncology, Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Division of Pediatric Hematology/Oncology, Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Kitai
authors.initials: K
authors.lastname: Kim
authors.affiliation: Division of Pediatric Hematology/Oncology, Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Marcella
authors.initials: M
authors.lastname: Cesana
authors.affiliation: Division of Pediatric Hematology/Oncology, Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Powers
authors.affiliation: Division of Pediatric Hematology/Oncology, Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Sutheera
authors.initials: S
authors.lastname: Ratanasirintrawoot
authors.affiliation: Division of Pediatric Hematology/Oncology, Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Tamer
authors.initials: T
authors.lastname: Onder
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Shibue
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA; Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
authors.affiliation: Division of Pediatric Hematology/Oncology, Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D008164:Luminescent Proteins; D035683:MicroRNAs; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C542687:mirnlet7 microRNA, mouse