title: BRG1 Governs Nanog Transcription in Early Mouse Embryos and Embryonic Stem Cells via Antagonism of Histone H3 Lysine 9/14 Acetylation.
abstract: During mouse preimplantation development, the generation of the inner cell mass (ICM) and trophoblast lineages comprises upregulation of Nanog expression in the ICM and its silencing in the trophoblast. However, the underlying epigenetic mechanisms that differentially regulate Nanog in the first cell lineages are poorly understood. Here, we report that BRG1 (Brahma-related gene 1) cooperates with histone deacetylase 1 (HDAC1) to regulate Nanog expression. BRG1 depletion in preimplantation embryos and Cdx2-inducible embryonic stem cells (ESCs) revealed that BRG1 is necessary for Nanog silencing in the trophoblast lineage. Conversely, in undifferentiated ESCs, loss of BRG1 augmented Nanog expression. Analysis of histone H3 within the Nanog proximal enhancer revealed that H3 lysine 9/14 (H3K9/14) acetylation increased in BRG1-depleted embryos and ESCs. Biochemical studies demonstrated that HDAC1 was present in BRG1-BAF155 complexes and BRG1-HDAC1 interactions were enriched in the trophoblast lineage. HDAC1 inhibition triggered an increase in H3K9/14 acetylation and a corresponding rise in Nanog mRNA and protein, phenocopying BRG1 knockdown embryos and ESCs. Lastly, nucleosome-mapping experiments revealed that BRG1 is indispensable for nucleosome remodeling at the Nanog enhancer during trophoblast development. In summary, our data suggest that BRG1 governs Nanog expression via a dual mechanism involving histone deacetylation and nucleosome remodeling.
authors.affiliation: Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University, East Lansing, Michigan, USA Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Carey
authors.affiliation: Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Zubing
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Inchul
authors.initials: I
authors.lastname: Choi
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute of Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Avishek
authors.initials: A
authors.lastname: Ganguly
authors.affiliation: Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Wilson
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute of Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Soumen
authors.initials: S
authors.lastname: Paul
authors.affiliation: Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University, East Lansing, Michigan, USA Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan, USA knottj@msu.edu.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Knott
mesh_terms: D000107:Acetylation; D000818:Animals; D001755:Blastocyst / Q000378:metabolism*; D053624:Blastocyst Inner Cell Mass / Q000166:cytology / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D014327:Trophoblasts / Q000166:cytology
chemical_list: D006657:Histones; D018398:Homeodomain Proteins; D046912:Multiprotein Complexes; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C491090:Smarcc1 protein, mouse; D014157:Transcription Factors; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; C513194:Smarca4 protein, mouse; D004265:DNA Helicases