Benetti Roberta, Gonzalo Susana, Jaco Isabel, Muñoz Purificación, Gonzalez Susana, Schoeftner Stefan, Murchison Elizabeth, Andl Thomas, Chen Taiping, Klatt Peter, Li En, Serrano Manuel, Millar Sarah, Hannon Gregory, Blasco Maria A
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 3 Melchor Fernández Almagro, Madrid E-28029, Spain.
Nat Struct Mol Biol. 2008 Mar;15(3):268-79. doi: 10.1038/nsmb.1399. Epub 2008 Mar 2.
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.
Dicer通过生成参与各种沉默途径的小RNA来启动RNA干扰。Dicer参与着丝粒沉默，但其在其他染色质结构域的表观遗传调控中的作用尚未得到探索。在这里，我们表明小家鼠中Dicer1的缺失会导致DNA甲基化减少，同时端粒重组增加和端粒延长。这些DNA甲基化缺陷与DNA甲基转移酶（Dnmts）Dnmt1、Dnmt3a和Dnmt3b的表达降低相关，并且通过它们的过表达可以恢复甲基化水平。我们确定视网膜母细胞瘤样2蛋白（Rbl2）是导致Dicer1缺失细胞中Dnmt表达降低的原因，这表明存在靶向Rbl2的Dicer依赖性小RNA。我们确定miR-290簇在Dicer1缺陷细胞中下调，并表明它使Rbl2沉默，从而控制Dnmt表达。这些结果确定了一条途径，通过该途径miR-290直接调节Rbl2依赖性Dnmt表达，间接影响端粒长度稳态。
