MULTI_FOLDS · Not one but many: adopting structural flexibility in the analysis of the evolution of lncRNAs.

Not one but many: adopting structural flexibility in the analysis of the evolution of lncRNAs.

Long non-coding RNAs (lncRNAs) are abundant in mammalian transcriptomes. However, it remains unclear how many of them are functional and how their functions are performed. LncRNAs seem to be poorly conserved at the sequence level, but some of them share conserved structural elements and are present at syntenic genomic locations in different species. A recent study revealed that secondary structure constrains sequence variation in lncRNAs. This is in contrast with previous analyses that dismissed relationships between structure and sequence evolution in lncRNAs. A crucial difference in the previous study is that the considered structural feature, accessibility, is computed from an ensemble of thermodynamically stable structures. Our group recently developed a novel Illumina-based implementation of in-vitro parallel probing of RNA structures called nextPARS. Using this technique, we observed that many lncRNA sites exhibit positive signals for both single- and double-strand specific enzymes, suggesting several structures may coexist. Based on this, we argue that the difficulty of identifying links between sequence and structure in lncRNAs results in part from limitations imposed by assuming a single, stable structure. To solve this, we developed a computational framework that enables the reconstruction of co-existing lncRNA structures from nextPARS or similar empirical data, and the comparison of such reconstructed ensembles from different species. The main goal of my research project is to study lncRNAs structures from animals and fungi. Using the model that enables the reconstruction of co-existing structures, I’ve investigated lncRNAs from different species for which experimental data from RNA structure probing has been obtained. I found that lncRNAs in different species share common structural elements, despite high sequence divergence, suggesting that lncRNAs may rely on short functional elements rather than long stretches of conserved sequences. This novel multidisciplinary approach establishes a framework for understanding the evolution of lncRNAs and should help to fill the gap between the structure and function of lncRNAs in different species.

Data: CORDIS, © European Union