2. Academic Validation
  3. A Network of Noncoding Regulatory RNAs Acts in the Mammalian Brain

A Network of Noncoding Regulatory RNAs Acts in the Mammalian Brain

  • Cell. 2018 Jul 12;174(2):350-362.e17. doi: 10.1016/j.cell.2018.05.022.
Benjamin Kleaveland 1,  Charlie Y Shi 2,  Joanna Stefano 2,  David P Bartel 3
Affiliations

Affiliations

  • 1 Howard Hughes Medical Institute, Cambridge, MA 02142, USA; Whitehead Institute of Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA.
  • 2 Howard Hughes Medical Institute, Cambridge, MA 02142, USA; Whitehead Institute of Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 3 Howard Hughes Medical Institute, Cambridge, MA 02142, USA; Whitehead Institute of Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].
PMID: 29887379 DOI: 10.1016/j.cell.2018.05.022
Abstract

Noncoding RNAs (ncRNAs) play increasingly appreciated gene-regulatory roles. Here, we describe a regulatory network centered on four ncRNAs-a long ncRNA, a circular RNA, and two microRNAs-using gene editing in mice to probe the molecular consequences of disrupting key components of this network. The long ncRNA Cyrano uses an extensively paired site to miR-7 to trigger destruction of this MicroRNA. Cyrano-directed miR-7 degradation is much more effective than previously described examples of target-directed MicroRNA degradation, which come primarily from studies of artificial and viral RNAs. By reducing miR-7 levels, Cyrano prevents repression of miR-7-targeted mRNAs and enables accumulation of Cdr1as, a circular RNA known to regulate neuronal activity. Without Cyrano, excess miR-7 causes cytoplasmic destruction of Cdr1as in neurons, in part through enhanced slicing of Cdr1as by a second miRNA, miR-671. Thus, several types of ncRNAs can collaborate to establish a sophisticated regulatory network.

Keywords

TDMD; circRNA; lncRNA knockout; mammalian gene regulation; miRNA knockout; miRNA tailing; miRNA target-site disruption; miRNA trimming; noncoding RNA; regulatory network.

Figures