While we are accustomed to seeing soccer players stroking a ball up and down grassy white-lined pitches and actors waltzing down the red carpet wearing a sharp suit or a stunning dress, we occasionally read news of these mammalian “celebrities” spending time in what could be deemed “unknown territory”, such as the corner store or gas station. “What are they doing there?” we foolishly ask!
Similarly, mammalian microRNAs (or miRNAs for short) usually play starring roles in the cytosol as inhibitors of translation; however, several studies (e.g. Park et al. and Leucci et al.) have snapped miRNAs in the unusual territory of the cell nuclei where their exact role remains unknown. Researchers from the lab of Guillermo Barreto (Max-Planck-Institute for Heart and Lung Research, Germany) recently sought to uncover the role of miRNA in the nucleus by focusing on miRNA lethal 7d (Mirlet7d, let-7d) given a known association with lung disease, a research interest of the Barreto lab.
Incredibly, Singh and colleagues now report that Mirlet7d forms part of a larger non-coding RNA-protein complex (christened MiCEE) that controls the epigenetic silencing of bidirectionally-expressed genes (genes expressing a non-coding (nc) and a coding (c) RNA from the same site but in different directions) and influences global genome organization.
Here are all the crucial movements made by Mirlet7d in the unknown territory of the nucleus:
- Studies in mouse and human normal/cancer cells found Mirlet7d in the cytoplasm and nucleus
- Total RNA sequencing after miRNA pulldown in mouse lung epithelial cells demonstrates Mirlet7d binding to ncRNAs expressed from bidirectionally transcribed genes in both mouse and human normal/cancer cells
- Binding helps to reduce the expression of ncRNAs and coding RNAs from bidirectionally expressed genes
- The Mirlet7d–ncRNA duplex interacts with components of the RNA-degrading RNA exosome complex and gene-silencing polycomb repressive complex 2 (PRC2) to form the MiCEE complex
- The MiCEE complex then targets the corresponding bidirectionally transcribed gene
- The MiCEE complex promotes silencing of transcription by two distinct mechanisms
- Degradation of transcribed ncRNAs by the RNA exosome (silencing transcription in one direction)
- Induction of heterochromatin formation and gene silencing via lysine 27 histone H3 tri-methylation mediated by the PRC2 subunit EZH2 (silencing transcription in the other direction!)
- Finally, the authors note that proper MiCEE function maintains nucleolar structure and ribosomal RNA synthesis, and helps to tether regulated genes to the peri-nucleolar region to promote proper nucleolar organization
This fascinating new study furthers our appreciation of mammalian miRNA function in the unknown territory of the nucleus and introduces a new ncRNA-protein complex in MiCEE, whose study may prove fruitful to our current understanding on the epigenetic regulation of multiple cellular functions.
So leave those old studies in well-understood areas behind and take a step into the unknown at Nature Genetics, June 2018.