title: A late transition in somatic cell reprogramming requires regulators distinct from the pluripotency network.
abstract: Reprogramming of somatic cells to a pluripotent state via expression of Oct4, Klf4, Myc, and Sox2 is a multistep process involving phased changes in gene expression. Here, we focus on the later stages of reprogramming, termed maturation and stabilization. We show that the stabilization phase and the acquisition of pluripotency are dependent on the removal of transgene expression late in the maturation phase. Clonal analysis of cells undergoing reprogramming revealed subsets of stabilization-competent (SC) and stabilization-incompetent (SI) cells. SC clones acquire a competency gene-expression signature late in the maturation phase. Functional analysis of SC signature genes identified enhancers of the transition to the stabilization phase and a distinct subset of genes required for the maintenance of pluripotency. Thus, the acquisition and maintenance of pluripotency are regulated by distinct molecular networks, and a specific regulatory program not previously implicated in reprogramming is required for the transition to transgene independence.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Ontario M5S 1A8, Canada.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Golipour
authors.forename: Laurent
authors.initials: L
authors.lastname: David
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Gowtham
authors.initials: G
authors.lastname: Jayakumaran
authors.forename: Calley L
authors.initials: CL
authors.lastname: Hirsch
authors.forename: Dan
authors.initials: D
authors.lastname: Trcka
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics*; D002999:Clone Cells; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks / Q000235:genetics; D000090062:Kruppel-Like Factor 4; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics; D019076:Transgenes / Q000235:genetics
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D012333:RNA, Messenger; D014157:Transcription Factors