Conserved RNA-binding protein interactions mediate syntologous lncRNA functions

Syntologous long noncoding RNAs (lncRNAs) are loci with conserved genomic positions that often show little or no sequence similarity. Despite diverging primary sequences, lncRNA syntologs from distant species can carry out similar functions. However, determinants underlying conserved functions of syntologous lncRNA transcripts with no sequence similarity remain unknown. Using CASC15 and melanoma formation as a paradigm for fast evolving lncRNAs and their functions, we found that human and zebrafish CASC15 syntologs with no detectable sequence similarity retained their function across 450 million years of evolution. Similar to the casc15-deficient zebrafish, CASC15-mutant human melanoma cells show increased cell migration. Expression of human CASC15 in zebrafish rescues loss of casc15 function by attenuating melanoma formation. This conserved function is supported by a set of RNA-binding proteins, interacting with both zebrafish and human CASC15 transcripts. Together, our findings demonstrate that conserved RNA-protein interactions can define functions of rapidly evolving lncRNA transcripts.