A novel requirement for DROSHA in maintenance of mammalian CG methylation

作者：Stathopoulou Athanasia; Chhetri Jyoti B; Ambrose John C; Esteve Pierre Olivier; Ji Lexiang; Erdjument Bromage Hediye; Zhang Guoqiang; Neubert Thomas A; Pradhan Sriharsa; Herrero Javier; Schmitz Robert J; Ooi Steen K T

来源：Nucleic Acids Research, 2017, 45(16): 9398-9412.

DOI：10.1093/nar/gkx695

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.

• 出版日期2017-9-19