MicroRNA-145 Regulates OCT4, SOX2, and KLF4 and Represses Pluripotency in Human Embryonic Stem Cells

• Published in: Cell 2009-05, Vol.137 (4), p.647-658
• Main Authors: Xu, Na, Papagiannakopoulos, Thales, Pan, Guangjin, Thomson, James A., Kosik, Kenneth S.
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - metabolism; Cell Differentiation; Cell Line; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Gene Expression Regulation, Developmental; Humans; Kruppel-Like Transcription Factors - genetics; MicroRNAs - metabolism; Octamer Transcription Factor-3 - genetics; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; RNA; SOXB1 Transcription Factors - genetics; STEMCELL
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2009.02.038

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.