A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases

Benetti, R., Gonzalo, S., Jaco, I., Munoz, P., Gonzalez, S., Schoeftner, S., Murchison, E. P., Andl, T., Chen, T. P., Klatt, P., Li, E., Serrano, M., Millar, S., Hannon, G. J., Blasco, M. A. (2008) A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nature Structural & Molecular Biology, 15 (3). pp. 268-279. ISSN 1545-998515459993 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/18311151
DOI: 10.1038/nsmb.1399

Abstract

Dicer initiates RNA interference by generating small RNAs involved in various silencing pathways. Dicer participates in centromeric silencing, but its role in the epigenetic regulation of other chromatin domains has not been explored. Here we show that Dicer1 deficiency in Mus musculus leads to decreased DNA methylation, concomitant with increased telomere recombination and telomere elongation. These DNA-methylation defects correlate with decreased expression of Dnmt1, Dnmt3a and Dnmt3b DNA methyltransferases (Dnmts), and methylation levels can be recovered by their overexpression. We identify the retinoblastoma-like 2 protein (Rbl2) as responsible for decreased Dnmt expression in Dicer1-null cells, suggesting the existence of Dicer-dependent small RNAs that target Rbl2. We identify the miR-290 cluster as being downregulated in Dicer1-deficient cells and show that it silences Rbl2, thereby controlling Dnmt expression. These results identify a pathway by which miR-290 directly regulates Rbl2-dependent Dnmt expression, indirectly affecting telomere-length homeostasis.

Item Type: Paper
Uncontrolled Keywords: EMBRYONIC STEM-CELLS RETINOBLASTOMA GENE-PRODUCT MAJOR SATELLITE REPEATS H3 LYSINE-9 METHYLATION PERICENTRIC HETEROCHROMATIN CHROMOSOME ENDS ENZYME DICER MAINTENANCE MOUSE FAMILY
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA methylation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > telomeres
CSHL Authors:
Communities: CSHL labs > Hannon lab
Watson School > Publications
Depositing User: Matt Covey
Date Deposited: 26 Feb 2013 15:29
Last Modified: 22 Sep 2014 15:46
PMCID: PMC2990406
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27565

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