A novel requirement for DROSHA in maintenance of mammalian CG methylation.

Nucleic acids research 2017 Sep 19

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In mammals, faithful inheritance of genomic methylation patterns ensures proper gene regulation and cell behaviour, impacting normal development and fertility. Following establishment, genomic methylation patterns are transmitted through S-phase by the maintenance methyltransferase Dnmt1. Using a protein interaction screen, we identify Microprocessor component DROSHA as a novel DNMT1-interactor. Drosha-deficient embryonic stem (ES) cells display genomic hypomethylation that is not accounted for by changes in the levels of DNMT proteins. DNMT1-mediated methyltransferase activity is also reduced in these cells. We identify two transcripts that are specifically upregulated in Drosha- but not Dicer-deficient ES cells. Regions within these transcripts predicted to form stem-loop structures are processed by Microprocessor and can inhibit DNMT1-mediated methylation in vitro. Our results highlight DROSHA as a novel regulator of mammalian DNA methylation and we propose that DROSHA-mediated processing of RNA is necessary to ensure full DNMT1 activity. This adds to the DROSHA repertoire of non-miRNA dependent functions as well as implicating RNA in regulating DNMT1 activity and correct levels of genomic methylation. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Citation

Athanasia Stathopoulou, Jyoti B Chhetri, John C Ambrose, Pierre-Olivier Estève, Lexiang Ji, Hediye Erdjument-Bromage, Guoqiang Zhang, Thomas A Neubert, Sriharsa Pradhan, Javier Herrero, Robert J Schmitz, Steen K T Ooi. A novel requirement for DROSHA in maintenance of mammalian CG methylation. Nucleic acids research. 2017 Sep 19;45(16):9398-9412