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.

1. Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 3 Melchor Fernández Almagro, Madrid E-28029, Spain.
2. Radiation and Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park, 3rd Floor, St. Louis, Missouri 63108, USA.
3. Tumor Suppression Group, Molecular Oncology Program, CNIO, 3 Melchor Fernández Almagro, Madrid E-28029, Spain.
4. Cold Spring Harbor Laboratory, Cold Spring Harbor, 1 Bungtown Road, New York 11724, USA.
5. Department of Dermatology, University of Pennsylvania, M8D Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6100, USA.
6. Epigenetics Program, Novartis Institutes for Biomedical Research, USCA, 600-5C-146, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

Correspondence to: Maria A Blasco¹ e-mail: mblasco@cnio.es

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