MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells.

@article{citeulike:2470508, 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.}, address = {Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.}, author = {Sinkkonen, Lasse and Hugenschmidt, Tabea and Berninger, Philipp and Gaidatzis, Dimos and Mohn, Fabio and Artus-Revel, Caroline G G. and Zavolan, Mihaela and Svoboda, Petr and Filipowicz, Witold }, citeulike-article-id = {2470508}, doi = {10.1038/nsmb.1391}, issn = {1545-9985}, journal = {Nat Struct Mol Biol}, keywords = {epigenetics, es\_cells, methylation, mir-290\_cluster}, month = {March}, posted-at = {2008-03-10 10:34:49}, priority = {2}, title = {MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells.}, url = {http://dx.doi.org/10.1038/nsmb.1391}, year = {2008} }

TY - JOUR ID - citeulike:2470508 L3 - citeulike-article-id:2470508 TI - MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. JF - Nat Struct Mol Biol AD - Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. SN - 1545-9985 N2 - 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. KW - epigenetics KW - es_cells KW - methylation KW - mir-290_cluster AU - Sinkkonen, Lasse AU - Hugenschmidt, Tabea AU - Berninger, Philipp AU - Gaidatzis, Dimos AU - Mohn, Fabio AU - Artus-Revel, Caroline G AU - Zavolan, Mihaela AU - Svoboda, Petr AU - Filipowicz, Witold PY - 2008/03/02/ UR - http://dx.doi.org/10.1038/nsmb.1391 ER -