title: MiRNA-Mediated Regulation of the SWI/SNF Chromatin Remodeling Complex Controls Pluripotency and Endodermal Differentiation in Human ESCs.
abstract: MicroRNAs and chromatin remodeling complexes represent powerful epigenetic mechanisms that regulate the pluripotent state. miR-302 is a strong inducer of pluripotency, which is characterized by a distinct chromatin architecture. This suggests that miR-302 regulates global chromatin structure; however, a direct relationship between miR-302 and chromatin remodelers has not been established. Here, we provide data to show that miR-302 regulates Brg1 chromatin remodeling complex composition in human embryonic stem cells (hESCs) through direct repression of the BAF53a and BAF170 subunits. With the subsequent overexpression of BAF170 in hESCs, we show that miR-302's inhibition of BAF170 protein levels can affect the expression of genes involved in cell proliferation. Furthermore, miR-302-mediated repression of BAF170 regulates pluripotency by positively influencing mesendodermal differentiation. Overexpression of BAF170 in hESCs led to biased differentiation toward the ectoderm lineage during EB formation and severely hindered directed definitive endoderm differentiation. Taken together, these data uncover a direct regulatory relationship between miR-302 and the Brg1 chromatin remodeling complex that controls gene expression and cell fate decisions in hESCs and suggests that similar mechanisms are at play during early human development.
authors.affiliation: Chromatin and Gene Expression Group, Epigenetics and Stem Cell Biology Laboratory, Department of Health and Human Services.
authors.forename: Staton L
authors.initials: SL
authors.lastname: Wade
authors.affiliation: Chromatin and Gene Expression Group, Epigenetics and Stem Cell Biology Laboratory, Department of Health and Human Services.
authors.forename: Lee F
authors.initials: LF
authors.lastname: Langer
authors.affiliation: Integrative Bioinformatics Resource, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Ward
authors.affiliation: Chromatin and Gene Expression Group, Epigenetics and Stem Cell Biology Laboratory, Department of Health and Human Services.
authors.forename: Trevor K
authors.initials: TK
authors.lastname: Archer
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism*; D004707:Endoderm / Q000254:growth & development; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D039904:Pluripotent Stem Cells; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C116160:ACTL6A protein, human; D000199:Actins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C532169:MIRN302A microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C101682:SMARCC2 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: BAF170; Cell differentiation; Chromatin; Embryonic stem cells; MicroRNAs