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. When the regions flanking the miRNA coding sequence are highly methylated, the miRNAs are more highly expressed, have greater sequence conservation, and are more likely to drive cancer-related phenotypes than miRNAs encoded by unmethylated loci. We show that the removal of DNA methylation from miRNA loci leads to their downregulation. Further, we found that MeCP2 binding to methylated miRNA loci halts RNA polymerase II elongation, leading to enhanced processing of the primary miRNA by Drosha. Taken together, our data reveal that DNA methylation directly affects miRNA biogenesis.
Bibliographical noteFunding Information:
C.L. thanks the following for grant support: I-CORE Gene Regulation in Complex Human Disease, Center No. 41/11, Fritz Thyssen Stiftung, Marie Curie Career Integration Grants (CIG), and the Dalya Gridinger Fund. R.E.B. thanks the Charles Clore Foundation. S.P. was supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 726225). G.A. was supported by grants from the Israel Science Foundation (ISF 562/16, ISF 142/13, and ISF Bikura 838/10) and by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel’s Ministry of Science and Technology (MOST) (3-13112).
© 2019, The Author(s).