title: Foxd3 Promotes Exit from Naive Pluripotency through Enhancer Decommissioning and Inhibits Germline Specification.
abstract: Following implantation, mouse epiblast cells transit from a naive to a primed state in which they are competent for both somatic and primordial germ cell (PGC) specification. Using mouse embryonic stem cells as an in vitro model to study the transcriptional regulatory principles orchestrating peri-implantation development, here we show that the transcription factor Foxd3 is necessary for exit from naive pluripotency and progression to a primed pluripotent state. During this transition, Foxd3 acts as a repressor that dismantles a significant fraction of the naive pluripotency expression program through decommissioning of active enhancers associated with key naive pluripotency and early germline genes. Subsequently, Foxd3 needs to be silenced in primed pluripotent cells to allow re-activation of relevant genes required for proper PGC specification. Our findings therefore uncover a cycle of activation and deactivation of Foxd3 required for exit from naive pluripotency and subsequent PGC specification.
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Respuela
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
authors.forename: Miloš
authors.initials: M
authors.lastname: Nikolić
authors.affiliation: The Chemical Proteomics Center and State Key Laboratory of Drug Research, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
authors.forename: Minjia
authors.initials: M
authors.lastname: Tan
authors.affiliation: Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Frommolt
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
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.
authors.forename: Joanna
authors.initials: J
authors.lastname: Wysocka
authors.affiliation: Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany. Electronic address: aradaigl@uni-koeln.de.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Rada-Iglesias
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000166:cytology; D004742:Enhancer Elements, Genetic; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000502:physiology*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005854:Germ Cells / Q000166:cytology; D005855:Germ Layers / Q000166:cytology*; D018095:Germ-Line Mutation; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology*; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology*; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic
chemical_list: D051858:Forkhead Transcription Factors; C101757:Foxd3 protein, mouse; D012097:Repressor Proteins