title: FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity.
abstract: Early development is governed by the ability of pluripotent cells to retain the full range of developmental potential and respond accurately to developmental cues. This property is achieved in large part by the temporal and contextual regulation of gene expression by enhancers. Here, we evaluated regulation of enhancer activity during differentiation of embryonic stem to epiblast cells and uncovered the forkhead transcription factor FOXD3 as a major regulator of the developmental potential of both pluripotent states. FOXD3 bound to distinct sites in the two cell types priming enhancers through a dual-functional mechanism. It recruited the SWI/SNF chromatin remodeling complex ATPase BRG1 to promote nucleosome removal while concurrently inhibiting maximal activation of the same enhancers by recruiting histone deacetylases1/2. Thus, FOXD3 prepares cognate genes for future maximal expression by establishing and simultaneously repressing enhancer activity. Through switching of target sites, FOXD3 modulates the developmental potential of pluripotent cells as they differentiate.
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Raga
authors.initials: R
authors.lastname: Krishnakumar
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Amy F
authors.initials: AF
authors.lastname: Chen
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Marisol G
authors.initials: MG
authors.lastname: Pantovich
authors.affiliation: Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Danial
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Parchem
authors.affiliation: Office of Strategic Coordination, Division of Program Coordination, Planning, and Strategic Initiatives, and Office of Director, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Labosky
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: blellochr@stemcell.ucsf.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Blelloch
mesh_terms: D000107:Acetylation; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D019070:Cell Lineage; D004265:DNA Helicases / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C101757:Foxd3 protein, mouse; D006657:Histones; D009687:Nuclear Proteins; D009707:Nucleosomes; D012097:Repressor Proteins; D014157:Transcription Factors; D006655:Histone Deacetylases; C513194:Smarca4 protein, mouse; D004265:DNA Helicases