title: Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis.
abstract: Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kareta
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Gorges
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Sana
authors.initials: S
authors.lastname: Hafeez
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University, Stanford, CA 94305, USA.
authors.forename: Bérénice A
authors.initials: BA
authors.lastname: Benayoun
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Samuele
authors.initials: S
authors.lastname: Marro
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Anne-Flore
authors.initials: AF
authors.lastname: Zmoos
authors.affiliation: London Regional Cancer Program, Children's Research Institute, Western University, London, ON N6A 4L6, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cecchini
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Damek
authors.initials: D
authors.lastname: Spacek
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Luis F Z
authors.initials: LF
authors.lastname: Batista
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: O'Brien
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Ng
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Cheen Euong
authors.initials: CE
authors.lastname: Ang
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Dedeepya
authors.initials: D
authors.lastname: Vaka
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Artandi
authors.affiliation: London Regional Cancer Program, Children's Research Institute, Western University, London, ON N6A 4L6, Canada.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dick
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University, Stanford, CA 94305, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Brunet
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address: julsage@stanford.edu.
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305, USA; Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: wernig@stanford.edu.
authors.forename: Marius
authors.initials: M
authors.lastname: Wernig
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D065150:Cellular Reprogramming; D002843:Chromatin / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D055748:SOXB1 Transcription Factors