Conserved RNA-binding protein interactions mediate syntologous lncRNA functions

Abstract

ABSTRACTSyntologous 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. UsingCASC15and melanoma formation as a paradigm for fast evolving lncRNAs and their functions, we found that human and zebrafishCASC15syntologs with no detectable sequence similarity retained their function across 450 million years of evolution. Similar to thecasc15-deficient zebrafish,CASC15-mutant human melanoma cells show increased cell migration. Expression of humanCASC15in zebrafish rescues loss ofcasc15function by attenuating melanoma formation. This conserved function is supported by a set of RNA-binding proteins, interacting with both zebrafish and humanCASC15transcripts. Together, our findings demonstrate that conserved RNA-protein interactions can define functions of rapidly evolving lncRNA transcripts.