Structural determinants of the SINE B2 element embedded in the long non-coding RNA activator of translation AS Uchl1

Peter Podbevšek,Piero Carninci,Janez Plavec,Giovanni Bussi,Carlotta Bon,Sabine Reißer,Stefano Gustincich,Silvia Zucchelli,Laura Cimatti,Francesca Fasolo

doi:10.1038/s41598-017-14908-6

Abstract

Pervasive transcription of mammalian genomes leads to a previously underestimated level of complexity in gene regulatory networks. Recently, we have identified a new functional class of natural and synthetic antisense long non-coding RNAs (lncRNA) that increases translation of partially overlapping sense mRNAs. These molecules were named SINEUPs, as they require an embedded inverted SINE B2 element for their UP-regulation of translation. Mouse AS Uchl1 is the representative member of natural SINEUPs. It was originally discovered for its role in increasing translation of Uchl1 mRNA, a gene associated with neurodegenerative diseases. Here we present the secondary structure of the SINE B2 Transposable Element (TE) embedded in AS Uchl1. We find that specific structural regions, containing a short hairpin, are required for the ability of AS Uchl1 RNA to increase translation of its target mRNA. We also provide a high-resolution structure of the relevant hairpin, based on NMR observables. Our results highlight the importance of structural determinants in embedded TEs for their activity as functional domains in lncRNAs.

Highlights

Transposable elements (TEs) are mobile repetitive sequences that represent about 50% of the mammalian genomes
We have demonstrated that an embedded inverted SINE B2 element acts as a functional domain in antisense (AS) Uchl[1], an AS long non-coding RNAs (lncRNA) able to increase translation of partially-overlapping protein-coding sense Uchl[1] mRNA28
“exonized” or “embedded” SINE elements have been hypothesized to act as portable domains in lncRNAs, contributing to their biological functions[24,31,38]

Summary

Introduction

Transposable elements (TEs) are mobile repetitive sequences that represent about 50% of the mammalian genomes. Specific TEs can be regulatory DNA elements acting as promoters or enhancers[1,2,3] as well as platforms to recruit transcription factors and chromatin remodelling complexes[4,5,6] They can be natural sources of regulatory sequences, co-opted to rewire gene regulatory networks[7]. We have demonstrated that an embedded inverted SINE B2 (invSINEB2) element acts as a functional domain in antisense (AS) Uchl[1], an AS lncRNA able to increase translation of partially-overlapping protein-coding sense Uchl[1] mRNA28. Despite recent advances in supporting the functional role of embedded TEs as lncRNA domains, it still remains to be determined how these elements can retain a specific biological function despite very poor sequence conservation. A high-resolution structure of the hairpin has been derived based on NMR observables

Methods

Results

Conclusion