Research of the Month

June 2018

Nat Genet. 2018 Jun 4. doi: 10.1038/s41588-018-0139-3. [Epub ahead of print]

MiCEE is a ncRNA-protein complex that mediates epigenetic silencing and nucleolar organization

Singh I, Contreras A, Cordero J, Rubio K, Dobersch S, Günther S, Jeratsch S, Mehta A, Krüger M, Graumann J, Seeger W, Dobreva G, Braun T, Barreto G

The majority of the eukaryotic genome is transcribed into noncoding RNAs (ncRNAs), which are important regulators of different nuclear processes by controlling chromatin structure. However, the full extent of ncRNA function has remained elusive. Here we deciphered the function of the microRNA Mirlet7d as a key regulator of bidirectionally transcribed genes. We found that nuclear Mirlet7d binds ncRNAs expressed from these genes. Mirlet7d-ncRNA duplexes are further bound by C1D, which in turn targets the RNA exosome complex and the polycomb repressive complex 2 (PRC2) to the bidirectionally active loci. The exosome degrades the ncRNAs, whereas PRC2 induces heterochromatin and transcriptional silencing through EZH2. Moreover, this multicomponent RNA-protein complex, which we named MiCEE, tethers the regulated genes to the perinucleolar region and thus is required for proper nucleolar organization. Our study demonstrates that the MiCEE complex mediates epigenetic silencing of bidirectionally expressed genes and global genome organization.

Our study highlights a novel mechanism of miRNA-induced transcriptional gene silencing. So far, the function of miRNAs was primarily seen in the cytoplasm where miRNAs repress gene expression at the posttranscriptional level. Hence, our discovery that Mirlet7d plays a crucial role in the cell nucleus by directing the RNA exosome complex to specific gene loci tagged by the expression of ncRNAs is conceptually novel. We believe that our finding will open a new chapter in the understanding of miRNA biology tying together the function of miRNAs and lncRNAs for gene silencing.

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