DNA methylation directs microRNA biogenesis in mammalian cells

Ohad Glaich, Shivang Parikh, Rachel E. Bell, Keren Mekahel, Maya Donyo, Yodfat Leader, Ronna Shayevitch, Danna Sheinboim, Sivan Yannai, Dror Hollander, Ze’ev Melamed, Galit Lev-Maor, Gil Ast () and Carmit Levy ()
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Ohad Glaich: Sackler Faculty of Medicine
Shivang Parikh: Sackler Faculty of Medicine
Rachel E. Bell: Sackler Faculty of Medicine
Keren Mekahel: Sackler Faculty of Medicine
Maya Donyo: Sackler Faculty of Medicine
Yodfat Leader: Sackler Faculty of Medicine
Ronna Shayevitch: Sackler Faculty of Medicine
Danna Sheinboim: Sackler Faculty of Medicine
Sivan Yannai: Sackler Faculty of Medicine
Dror Hollander: Sackler Faculty of Medicine
Ze’ev Melamed: Sackler Faculty of Medicine
Galit Lev-Maor: Sackler Faculty of Medicine
Gil Ast: Sackler Faculty of Medicine
Carmit Levy: Sackler Faculty of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13527-1

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