A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases.
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.
Benetti
Roberta
R
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 3 Melchor Fernández Almagro, Madrid E-28029, Spain.
Gonzalo
Susana
S
Jaco
Isabel
I
Muñoz
Purificación
P
Gonzalez
Susana
S
Schoeftner
Stefan
S
Murchison
Elizabeth
E
Andl
Thomas
T
Chen
Taiping
T
Klatt
Peter
P
Li
En
E
Serrano
Manuel
M
Millar
Sarah
S
Hannon
Gregory
G
Blasco
Maria A
MA
D000818:Animals; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D004722:Endoribonucleases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D011995:Recombination, Genetic; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism*; D043244:Ribonuclease III; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D053487:DEAD-box RNA Helicases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D004722:Endoribonucleases; D006657:Histones; D035683:MicroRNAs; D050717:Retinoblastoma-Like Protein p130; D043244:Ribonuclease III; D019098:Telomerase; D000097584:DNA Methyltransferase 3B; C493838:Rbl2 protein, mouse; C000619381:Dnmt1 protein, mouse; C509781:Dicer1 protein, mouse