LincRNA cyrano hijacks miRNA/Argonaute complex for a novel, non-canonical function indispensable to early development

Hosted by Professor Chris Ponting.

If you have a question about this talk, please contact Emily Frape.

Thousands of long intervening noncoding RNAs (lincRNAs) have been recently identified in human and mouse. To better understand functions and evolution of these enigmatic RNAs, we identified more than 550 lincRNAs in zebrafish, an established vertebrate model for development. Although zebrafish lincRNAs shared many characteristics with mammalian lincRNAs, only 29 had detectable sequence similarity with putative mammalian counterparts, typically restricted to a single short region of high conservation. We showed that perturbations of deeply conserved lincRNAs caused developmental abnormalities in zebrafish embryos including brain morphogenesis defects and neurogenesis. The developmental defects could be rescued by either the mature zebrafish lincRNA or its human or mouse othologs. Our rescue experiments showed that despite limited sequence conservation, lincRNAs have conserved functions in zebrafish and mammals.

We recognized that the conserved region of one of the lincRNAs that we called cyrano contains a highly complementary, near perfect miR-7 site that is bound by Argonaute proteins and is highly conserved in all examined vertebrates. We show that a near perfect pairing to a miRNA is indispensable to the cyrano function in vivo. Although miR-7 appears to modestly regulate cyrano levels, it cannot explain the unusual high complementarity of the miRNA—lincRNA pairing. Loss of function and rescue assays in zebrafish embryos show that the interaction between miR-7 and cyrano differs from the canonical miRNA—target regulation suggesting that lincRNA—miRNA complex has an additional, novel function indispensible for normal development.