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; Carmit Levy

doi:10.1038/s41467-019-13527-1

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^*, Carmit Levy

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

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.

Original language	American English
Article number	5657
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13527-1
State	Published - 1 Dec 2019
Externally published	Yes

Bibliographical note

Funding 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).

Publisher Copyright:
© 2019, The Author(s).

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title = "DNA methylation directs microRNA biogenesis in mammalian cells",

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.",

author = "Ohad Glaich and Shivang Parikh and Bell, {Rachel E.} and Keren Mekahel and Maya Donyo and Yodfat Leader and Ronna Shayevitch and Danna Sheinboim and Sivan Yannai and Dror Hollander and Ze{\textquoteright}ev Melamed and Galit Lev-Maor and Gil Ast and Carmit Levy",

note = "Funding 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{\textquoteright}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{\textquoteright}s Ministry of Science and Technology (MOST) (3-13112). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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AU - Shayevitch, Ronna

AU - Sheinboim, Danna

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AU - Hollander, Dror

AU - Melamed, Ze’ev

AU - Lev-Maor, Galit

AU - Ast, Gil

AU - Levy, Carmit

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N2 - 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.

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DNA methylation directs microRNA biogenesis in mammalian cells

Abstract

Bibliographical note

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