A novel requirement for DROSHA in maintenance of mammalian CG methylation | Zendy

Αθανασία Σταθοπούλου | Zendy; Jyoti Chhetri | Zendy; John C. Ambrose | Zendy; PierreOlivier Estève | Zendy; Lexiang Ji | Zendy; Hediye ErdjumentBromage | Zendy; Guoqiang Zhang | Zendy; Thomas A. Neubert | Zendy; Sriharsa Pradhan | Zendy; Javier Herrero | Zendy; Robert J. Schmitz | Zendy; Steen K.T. Ooi | Zendy

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A novel requirement for DROSHA in maintenance of mammalian CG methylation

Author(s) -

Αθανασία Σταθοπούλου,

Jyoti Chhetri,

John C. Ambrose,

PierreOlivier Estève,

Lexiang Ji,

Hediye ErdjumentBromage,

Guoqiang Zhang,

Thomas A. Neubert,

Sriharsa Pradhan,

Javier Herrero,

Robert J. Schmitz,

Steen K.T. Ooi

Publication year - 2017

Publication title -

nucleic acids research

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 9.008

H-Index - 537

eISSN - 1362-4954

pISSN - 0305-1048

DOI - 10.1093/nar/gkx736

Subject(s) - drosha , biology , dna methylation , dnmt1 , dna methyltransferase , dicer , methylation , methyltransferase , genetics , microbiology and biotechnology , microrna , rna , rna interference , gene expression , gene

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.

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