title: Ground State Conditions Induce Rapid Reorganization of Core Pluripotency Factor Binding before Global Epigenetic Reprogramming.
abstract: Mouse embryonic stem cells (mESCs) cultured under serum/LIF conditions exhibit heterogeneous expression of pluripotency-associated factors that can be overcome by two inhibitors (2i) of the MEK and GSK3 pathways. Several studies have shown that the "ground state" induced by 2i is characterized by global hypomethylation and specific transcriptional profiles, but little is known about the contributing effectors. Here we show that 2i conditions rapidly alter the global binding landscape of OCT4, SOX2, and NANOG. The dynamic binding influences enhancer activity and shows enrichment for regulators linked to Wnt and Erk signaling. Epigenomic characterization provided limited insights to the immediate transcriptional dynamics, suggesting that these are likely more secondary effects. Likewise, loss of the PRC2 component EED to prevent H3K27me3 deposition had minimal effect on the transcriptome, implying that it is largely dispensable for continued repression of bivalent genes and de novo silencing in 2i.
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Galonska
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ziller
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Karnik
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: alexander_meissner@harvard.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000502:physiology*; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: C107275:Eed protein, mouse; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D063151:Polycomb Repressive Complex 2; D038362:Glycogen Synthase Kinase 3; D048369:MAP Kinase Kinase 1