Ancient exapted transposable elements promote nuclear enrichment of long noncoding RNAs

Abstract

The sequence domains underlying long noncoding RNA (lncRNA) activities, including their characteristic nuclear enrichment, remain largely unknown. It has been proposed that these domains can originate from neofunctionalised fragments of transposable elements (TEs), otherwise known as RIDLs (Repeat Insertion Domains of Long Noncoding RNA), although just a handful have been identified. It is challenging to distinguish functional RIDL instances against a numerous genomic background of neutrally-evolving TEs. We here show evidence that a subset of TE types experience evolutionary selection in the context of lncRNA exons. Together these comprise an enrichment group of 5374 TE fragments in 3566 loci. Their host lncRNAs tend to be functionally validated and associated with disease. This RIDL group was used to explore the relationship between TEs and lncRNA subcellular localisation. Using global localisation data from ten human cell lines, we uncover a dose-dependent relationship between nuclear/cytoplasmic distribution, and evolutionarily-conserved L2b, MIRb and MIRc elements. This is observed in multiple cell types, and is unaffected by confounders of transcript length or expression. Experimental validation with engineered transgenes shows that these TEs drive nuclear enrichment in a natural sequence context. Together these data reveal a role for TEs in regulating the subcellular localisation of lncRNAs.