DNA methylation directs microRNA biogenesis

MicroRNA (miRNA) biogenesis initiates co-transcriptionally, but how the Microprocessor machinery pinpoints the locations of short precursor miRNA sequences within long flanking regions of the transcript is not known. Here we show that miRNA biogenesis depends on DNA methylation. We found that miRNAs whose corresponding coding sequence’s flanking regions are highly methylated are expressed more, have greater sequence conservation, and are more likely to drive cancer-related phenotypes than miRNAs encoded by unmethylated loci. Accordingly, the removal of DNA methylation from miRNAs leads to their downregulation. Further, we found that MeCP2 binding to the DNA of methylated miRNAs halts RNA polymerase II elongation, an inactivation that leads to enhanced processing of primary miRNA by Drosha. Taken together, our data reveal that DNA methylation directly affects miRNA biogenesis. miRNA profiling in mouse ESC(R1) and in mouse ESC without DMNTs(TKO). R1 and TKO cells were obtain from: Akiko Tsumura et al, Maintenance of self‐renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b (Genes to Cell 2006). Two biological replicates were performed for the miRNA profiling.