title: MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells.
abstract: MicroRNAs (miRNAs) are posttranscriptional modulators of gene expression and play an important role in many developmental processes. We report here that expression of microRNA-145 (miR-145) is low in self-renewing human embryonic stem cells (hESCs) but highly upregulated during differentiation. We identify the pluripotency factors OCT4, SOX2, and KLF4 as direct targets of miR-145 and show that endogenous miR-145 represses the 3' untranslated regions of OCT4, SOX2, and KLF4. Increased miR-145 expression inhibits hESC self-renewal, represses expression of pluripotency genes, and induces lineage-restricted differentiation. Loss of miR-145 impairs differentiation and elevates OCT4, SOX2, and KLF4. Furthermore, we find that the miR-145 promoter is bound and repressed by OCT4 in hESCs. This work reveals a direct link between the core reprogramming factors and miR-145 and uncovers a double-negative feedback loop involving OCT4, SOX2, KLF4, and miR-145.
authors.affiliation: Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, The University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Xu
authors.forename: Thales
authors.initials: T
authors.lastname: Papagiannakopoulos
authors.forename: Guangjin
authors.initials: G
authors.lastname: Pan
authors.forename: James A
authors.initials: JA
authors.lastname: Thomson
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kosik
mesh_terms: D020413:3' Untranslated Regions / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D035683:MicroRNAs / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors