title: Reorganization of enhancer patterns in transition from naive to primed pluripotency.
abstract: Naive and primed pluripotency is characterized by distinct signaling requirements, transcriptomes, and developmental properties, but both cellular states share key transcriptional regulators: Oct4, Sox2, and Nanog. Here, we demonstrate that transition between these two pluripotent states is associated with widespread Oct4 relocalization, mirrored by global rearrangement of enhancer chromatin landscapes. Our genomic and biochemical analyses identified candidate mediators of primed state-specific Oct4 binding, including Otx2 and Zic2/3. Even when differentiation cues are blocked, premature Otx2 overexpression is sufficient to exit the naive state, induce transcription of a substantial subset of primed pluripotency-associated genes, and redirect Oct4 to previously inaccessible enhancer sites. However, the ability of Otx2 to engage new enhancer regions is determined by its levels, cis-encoded properties of the sites, and the signaling environment. Our results illuminate regulatory mechanisms underlying pluripotency and suggest that the capacity of transcription factors such as Otx2 and Oct4 to pioneer new enhancer sites is highly context dependent.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Christa
authors.initials: C
authors.lastname: Buecker
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Rajini
authors.initials: R
authors.lastname: Srinivasan
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Calo
authors.affiliation: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," CNR, Via P. Castellino, 111, 80131 Naples, Italy; IRCCS Neuromed, 86077 Pozzilli (IS), Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Acampora
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Tiago
authors.initials: T
authors.lastname: Faial
authors.affiliation: Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," CNR, Via P. Castellino, 111, 80131 Naples, Italy; IRCCS Neuromed, 86077 Pozzilli (IS), Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Simeone
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Minjia
authors.initials: M
authors.lastname: Tan
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: swigut@stanford.edu.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Swigut
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: wysocka@stanford.edu.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wysocka
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D051857:Otx Transcription Factors / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D050814:Octamer Transcription Factor-3; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; C494174:Pou5f1 protein, mouse