Phylogenetic Study of Long Non-Coding RNA NEAT1 and MALAT1 to Infer Structural-Functional Connection

Abstract

NEAT1 and MALAT1 are the only two lncRNAs that utilise the tRNA-processing machinery for their maturation, coded very close to each other yet differing in function and evolutionary conservation. Here, we identified NEAT1 and MALAT1 orthologs in 545 mammals and studied their conservation patterns to gain functional insights. In the functional basis of NEAT1Long, we found G-quadruplexes and short sequence motifs that interact with the DSHS family of proteins and TDP-43, as well as gene length and self-complementary regions that further stabilise paraspeckle integrity. We found that transposable elements play a crucial role in NEAT1 evolution by contributing structures recognised by DSHS proteins. We identified the NEAT1Short isoform in all NEAT1 orthologs, and our results suggest its distinct functional role. Our findings also support the conservation of the isoform switch mechanism mediated by TDP-43. The function of MALAT1 is likely based on its highly conserved primary sequence, and we demonstrated the gene regions under stronger purifying selection. This is the first large-scale phylogenetic study of NEAT1 - a lncRNAs that lack sequence similarity between orthologs while maintaining functional and syntenic conservation.