Article abstract
Nature Structural & Molecular Biology 15, 259 - 267 (2008)
Published online: 2 March 2008 | doi:10.1038/nsmb.1391
MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells
Lasse Sinkkonen1, Tabea Hugenschmidt1, Philipp Berninger2, Dimos Gaidatzis2, Fabio Mohn1, Caroline G Artus-Revel1, Mihaela Zavolan2, Petr Svoboda3 & Witold Filipowicz1
Abstract
Loss of microRNA (miRNA) pathway components negatively affects differentiation of embryonic stem (ES) cells, but the underlying molecular mechanisms remain poorly defined. Here we characterize changes in mouse ES cells lacking Dicer (Dicer1). Transcriptome analysis of Dicer-/- cells indicates that the ES-specific miR-290 cluster has an important regulatory function in undifferentiated ES cells. Consistently, many of the defects in Dicer-deficient cells can be reversed by transfection with miR-290 family miRNAs. We demonstrate that Oct4 (also known as Pou5f1) silencing in differentiating Dicer-/- ES cells is accompanied by accumulation of repressive histone marks but not by DNA methylation, which prevents the stable repression of Oct4. The methylation defect correlates with downregulation of de novo DNA methyltransferases (Dnmts). The downregulation is mediated by Rbl2 and possibly other transcriptional repressors, potential direct targets of miR-290 cluster miRNAs. The defective DNA methylation can be rescued by ectopic expression of de novo Dnmts or by transfection of the miR-290 cluster miRNAs, indicating that de novo DNA methylation in ES cells is controlled by miRNAs.
- Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
- Division of Bioinformatics, Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland, and the Swiss Institute of Bioinformatics.
- Institute of Molecular Genetics, Videnska 1083, Prague, Czech Republic.
Correspondence to: Witold Filipowicz1 e-mail: filipowi@fmi.ch
Correspondence to: Petr Svoboda3 e-mail: svobodap@img.cas.cz
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